The reversible reproductive toxicity of 5-fluorouracil in mice

Naren, Gerile; Wang, Lu; Zhang, Xiaolei; Cheng, Lijuan; Yang, Shuai; Yang, Jiajie; Guo, Jianzhong; Nashun, Buhe

doi:10.1016/j.reprotox.2021.02.002

Cited by 12 publications

(12 citation statements)

References 31 publications

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“…77,[79][80][81] Previous experiments showed that after intraperitoneal administration of 50 mg/kg/day 5FU for 4 days, the ovarian size was remarkably diminished compared to the control group (Table 3). 8 In another research, 5FU caused significant reduction of body weight and ovarian wet weight to body weight ratio in female rats. 82…”

Section: Effect Of 5fu On Ovarian Sizementioning

confidence: 92%

“…Unlike the control ovaries, no enlarged ampulla and mature oocyte was seen in the ovaries of 5FU-treated mice (Table 3). 8 As secondary and antral follicles have rapidly dividing cells, including oocytes and granulosa cells, they are more vulnerable to 5FU-induced toxicity. Although observing growing follicles being atretic in the ovary is a normal physiological phenomenon, in a prior intervention, the 5FU-treated ovaries demonstrated a considerable elevation in the amount of morphologically atretic secondary and antral follicles (Figure 2).…”

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

confidence: 99%

“…83 At last, according to almost all the previous studies, it is allegedly true that 5FU leads to a significant reduction in the amount and a notable deficiency in the maturation of growing follicles. 8,78,84 Effect of 5FU on primordial and primary follicles It should be stated that, in some studies, the count of primordial and primary follicles had no remarkable differences between 5FU-treated and control ovaries which meant that 5FU did not significantly affect primordial and primary follicles. 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.…”

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

confidence: 99%

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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 Sizementioning

confidence: 92%

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

confidence: 99%

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

confidence: 99%

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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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“…However, these defects could be recovered and no obvious abnormality was observed in their offspring, suggesting that the adverse effects could be reversed following withdrawal of 5-FU administration (Ref. 50 ). In addition to self-recovery, combined administration of triptorelin, a GnRH agonist often used as a hormone responsive anti-cancer drug, alleviates 5-FU-induced follicle number reduction, probably via decreasing the levels of E2, follicle-stimulating hormone (FSH), Bax and nuclear factor (NF)-κB, and increasing the levels of anti-Müllerian hormone (AMH) and Bcl-2 in the serum (Ref.…”

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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“…FU (50mg/kg/day for 4 days) does not alter primordial follicle number in vivo in mice, but depletes growing follicles. Additionally, oocyte maturation and early embryo development is impaired in vitroNaren et al (2021) Single-dose (450mg/kg) 5-FU significantly reduces the number of follicles in all classes in vivo in mice, including primordial folliclesAlmeida et al (2021)…”

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confidence: 99%

The future of fertility preservation for women treated with chemotherapy

Alesi

Nguyen

Stringer

et al. 2023

Reproduction and Fertility

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Cytotoxic chemotherapies have been a mainstay of cancer treatment, but are associated with numerous systemic adverse effects, including impacts to fertility and endocrine health. Irreversible ovarian damage and follicle depletion are side-effects of chemotherapy that can lead to infertility and premature menopause, both being major concerns of young cancer patients. Notably, many women will proceed with fertility preservation, but unfortunately existing strategies don’t entirely solve the problem. Most significantly, oocyte and embryo freezing do not prevent cancer treatment-induced ovarian damage from occurring, which may result in the impairment of long-term hormone production. Unfortunately, loss of endogenous endocrine function is not fully restored by hormone replacement therapy. Additionally, while GnRH agonists are standard care for patients receiving alkylating chemotherapy to lessen the risk of premature menopause, their efficacy is incomplete. The lack of more broadly effective options stems, in part, from our poor understanding of how different treatments damage the ovary. Here, we summarise the impacts of two commonly utilised chemotherapies – cyclophosphamide and cisplatin – on ovarian function and fertility, and discuss the mechanisms underpinning this damage. Additionally, we critically analyse current research avenues in the development of novel fertility preservation strategies, with a focus on fertoprotective agents.

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The reversible reproductive toxicity of 5-fluorouracil in mice

Cited by 12 publications

References 31 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

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

The future of fertility preservation for women treated with chemotherapy

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