Vincristine Chemotherapy Induces Atresia of Growing Ovarian Follicles in Mice

Amy L. Winship, Melanie Carpenter, Meaghan Griffiths, Karla J. Hutt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

With great advances in cancer detection and treatment, patient survival rates have improved substantially. Subsequently, significant efforts are now focused on improving the long-term sequelae of anticancer therapies in survivors, which includes fertility. Vincristine is a microtubule destabilizing antimitotic chemotherapeutic agent commonly administered for the treatment of cancers or autoimmune disorders prevalent in girls and women of reproductive age. The potential off-target effects of vincristine on the ovary have not been directly examined. Eight-week and 6-month-old C57BL/6J mice were administered with vincristine (1 mg/kg/bw/day) or saline on day (d)1, d4, and d8, then sacrificed after 24 hours (h), or 14 days (n = 4-6/group). We assessed the impact of vincristine on the ovarian reserve of quiescent primordial follicles, as well as growing follicles, which produce mature ovulatory oocytes. This study clearly demonstrated that multidose vincristine administration caused acute atresia and loss of growing follicles and reduced corpora luteua counts 24 h following final treatment. Treatment also disrupted estrous cycling and reduced serum anti-Müllerian hormone levels. However, primordial follicle numbers were unaffected, and growing follicle populations were restored to control levels 14 days after final treatment. Vincristine exerted similar effects on ovarian follicle populations in both 8-week-old reproductively young mice and reproductively older 6-month-old mice. This study suggests that vincristine, administrated at the current dose, is toxic to growing follicles but does not deplete primordial follicles in mice. Further studies should be performed before extrapolating these data to infer the consequences of vincristine on the ovary in humans.

Original languageEnglish
Pages (from-to)43-53
Number of pages11
JournalToxicological sciences : an official journal of the Society of Toxicology
Volume169
Issue number1
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • chemotherapy
  • follicle
  • oncofertility
  • ovary
  • ovotoxicity

Cite this

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title = "Vincristine Chemotherapy Induces Atresia of Growing Ovarian Follicles in Mice",
abstract = "With great advances in cancer detection and treatment, patient survival rates have improved substantially. Subsequently, significant efforts are now focused on improving the long-term sequelae of anticancer therapies in survivors, which includes fertility. Vincristine is a microtubule destabilizing antimitotic chemotherapeutic agent commonly administered for the treatment of cancers or autoimmune disorders prevalent in girls and women of reproductive age. The potential off-target effects of vincristine on the ovary have not been directly examined. Eight-week and 6-month-old C57BL/6J mice were administered with vincristine (1 mg/kg/bw/day) or saline on day (d)1, d4, and d8, then sacrificed after 24 hours (h), or 14 days (n = 4-6/group). We assessed the impact of vincristine on the ovarian reserve of quiescent primordial follicles, as well as growing follicles, which produce mature ovulatory oocytes. This study clearly demonstrated that multidose vincristine administration caused acute atresia and loss of growing follicles and reduced corpora luteua counts 24 h following final treatment. Treatment also disrupted estrous cycling and reduced serum anti-M{\"u}llerian hormone levels. However, primordial follicle numbers were unaffected, and growing follicle populations were restored to control levels 14 days after final treatment. Vincristine exerted similar effects on ovarian follicle populations in both 8-week-old reproductively young mice and reproductively older 6-month-old mice. This study suggests that vincristine, administrated at the current dose, is toxic to growing follicles but does not deplete primordial follicles in mice. Further studies should be performed before extrapolating these data to infer the consequences of vincristine on the ovary in humans.",
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Vincristine Chemotherapy Induces Atresia of Growing Ovarian Follicles in Mice. / Winship, Amy L.; Carpenter, Melanie; Griffiths, Meaghan; Hutt, Karla J.

In: Toxicological sciences : an official journal of the Society of Toxicology, Vol. 169, No. 1, 01.05.2019, p. 43-53.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Vincristine Chemotherapy Induces Atresia of Growing Ovarian Follicles in Mice

AU - Winship, Amy L.

AU - Carpenter, Melanie

AU - Griffiths, Meaghan

AU - Hutt, Karla J.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - With great advances in cancer detection and treatment, patient survival rates have improved substantially. Subsequently, significant efforts are now focused on improving the long-term sequelae of anticancer therapies in survivors, which includes fertility. Vincristine is a microtubule destabilizing antimitotic chemotherapeutic agent commonly administered for the treatment of cancers or autoimmune disorders prevalent in girls and women of reproductive age. The potential off-target effects of vincristine on the ovary have not been directly examined. Eight-week and 6-month-old C57BL/6J mice were administered with vincristine (1 mg/kg/bw/day) or saline on day (d)1, d4, and d8, then sacrificed after 24 hours (h), or 14 days (n = 4-6/group). We assessed the impact of vincristine on the ovarian reserve of quiescent primordial follicles, as well as growing follicles, which produce mature ovulatory oocytes. This study clearly demonstrated that multidose vincristine administration caused acute atresia and loss of growing follicles and reduced corpora luteua counts 24 h following final treatment. Treatment also disrupted estrous cycling and reduced serum anti-Müllerian hormone levels. However, primordial follicle numbers were unaffected, and growing follicle populations were restored to control levels 14 days after final treatment. Vincristine exerted similar effects on ovarian follicle populations in both 8-week-old reproductively young mice and reproductively older 6-month-old mice. This study suggests that vincristine, administrated at the current dose, is toxic to growing follicles but does not deplete primordial follicles in mice. Further studies should be performed before extrapolating these data to infer the consequences of vincristine on the ovary in humans.

AB - With great advances in cancer detection and treatment, patient survival rates have improved substantially. Subsequently, significant efforts are now focused on improving the long-term sequelae of anticancer therapies in survivors, which includes fertility. Vincristine is a microtubule destabilizing antimitotic chemotherapeutic agent commonly administered for the treatment of cancers or autoimmune disorders prevalent in girls and women of reproductive age. The potential off-target effects of vincristine on the ovary have not been directly examined. Eight-week and 6-month-old C57BL/6J mice were administered with vincristine (1 mg/kg/bw/day) or saline on day (d)1, d4, and d8, then sacrificed after 24 hours (h), or 14 days (n = 4-6/group). We assessed the impact of vincristine on the ovarian reserve of quiescent primordial follicles, as well as growing follicles, which produce mature ovulatory oocytes. This study clearly demonstrated that multidose vincristine administration caused acute atresia and loss of growing follicles and reduced corpora luteua counts 24 h following final treatment. Treatment also disrupted estrous cycling and reduced serum anti-Müllerian hormone levels. However, primordial follicle numbers were unaffected, and growing follicle populations were restored to control levels 14 days after final treatment. Vincristine exerted similar effects on ovarian follicle populations in both 8-week-old reproductively young mice and reproductively older 6-month-old mice. This study suggests that vincristine, administrated at the current dose, is toxic to growing follicles but does not deplete primordial follicles in mice. Further studies should be performed before extrapolating these data to infer the consequences of vincristine on the ovary in humans.

KW - chemotherapy

KW - follicle

KW - oncofertility

KW - ovary

KW - ovotoxicity

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U2 - 10.1093/toxsci/kfz022

DO - 10.1093/toxsci/kfz022

M3 - Article

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JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

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