Chemotherapy drugs cyclophosphamide, cisplatin and doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis

Smart, Eleanor; Lopes, Federica; Rice, Siobhan; Nagy, Boglarka; Anderson, Richard A.; Mitchell, Rod T; Spears, Norah

doi:10.1038/s41598-018-19761-9

Cited by 71 publications

(63 citation statements)

References 50 publications

(72 reference statements)

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“…No change in Leydig cells function and morphology has been observed in the pre-pubertal testis after 48 h in vitro exposure to doxorubicin [31]. Similarly, recent data have reported that Leydig cell density was unaffected after 24 h in vitro exposure to cisplatin, cyclophosphamide, and doxorubicin [24]. Although no change has been observed in rodent Leydig cells in in vitro studies, elevated LH levels found in survivors of paediatric cancer might suggest Leydig cell alteration; the few studies available do not currently allow conclusions to be drawn about the impact of chemotherapy exposure during childhood on testicular somatic cells.…”

Section: Effects Of Chemotherapy On Somatic Cellsmentioning

confidence: 81%

“…However, in contrast to germ cells, Sertoli cells seemed to develop a better resistance to chemotherapeutic agents in an animal model. In vitro studies using prepubertal rat testis showed no impact on the Sertoli cell number after 48 h exposure to doxorubicin, cisplatin, or cyclophosphamide [24]. Another study highlighted cell death resistance in primary Sertoli cells isolated from prepubertal rat, after 24 h in vitro exposure to cisplatin and etoposide.…”

Section: Effects Of Chemotherapy On Somatic Cellsmentioning

confidence: 99%

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Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

Delessard

Saulnier

Rives

et al. 2020

IJMS

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Over the last decade, the number of cancer survivors has increased thanks to progress in diagnosis and treatment. Cancer treatments are often accompanied by adverse side effects depending on the age of the patient, the type of cancer, the treatment regimen, and the doses. The testicular tissue is very sensitive to chemotherapy and radiotherapy. This review will summarize the epidemiological and experimental data concerning the consequences of exposure to chemotherapy during the prepubertal period or adulthood on spermatogenic progression, sperm production, sperm nuclear quality, and the health of the offspring. Studies concerning the gonadotoxicity of anticancer drugs in adult survivors of childhood cancer are still limited compared with those concerning the effects of chemotherapy exposure during adulthood. In humans, it is difficult to evaluate exactly the toxicity of chemotherapeutic agents because cancer treatments often combine chemotherapy and radiotherapy. Thus, it is important to undertake experimental studies in animal models in order to define the mechanism involved in the drug gonadotoxicity and to assess the effects of their administration alone or in combination on immature and mature testis. These data will help to better inform cancer patients after recovery about the risks of chemotherapy for their future fertility and to propose fertility preservation options.

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Section: Effects Of Chemotherapy On Somatic Cellsmentioning

confidence: 81%

Section: Effects Of Chemotherapy On Somatic Cellsmentioning

confidence: 99%

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

Delessard

Saulnier

Rives

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…For each analysis of every experimental treatment, all technical replicates from one patient were combined to give a single datapoint. Tissues were exposed to chemotherapy drugs for a short time period, as in previous work by us and others, to mimic the short period of exposure that patients usually experience each drug cycle (Morgan et al 2013, Lopes et al 2014, Lande et al 2017, Rossi et al 2017, Smart et al 2018. On Day 3 of culture, after 24 h of drug exposure, tissue from experimental treatments was moved to drug-free medium for 96 h, with medium changed after 48 h: Control tissue was kept in drug-free medium throughout, with medium changed at the same time as for experimental groups.…”

Section: Human Ovary Tissue Culturementioning

confidence: 99%

Single and combined effects of cisplatin and doxorubicin on the human and mouse ovary in vitro

et al. 2020

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Chemotherapy drugs are administered to patients using combination regimens, and as such the possibility of multiplicative effects between drugs need to be investigated. This study examines the individual and combined effects of the chemotherapy drugs cisplatin and doxorubicin on the human ovary. Although cisplatin and doxorubicin are known to affect female fertility, there is limited information about their direct effects on the human ovary, and none examining the possibility of combined, multiplicative effects of co-exposure to these drugs. Here, human ovarian biopsies were obtained from 14 women at the time of caesarean section, with 38 mouse ovaries also obtained from neonatal C57Bl/6J mice. Tissue was cultured for 6 days prior to analyses, with chemotherapy drugs added to culture medium on the second day of culture only. Treatment groups of a single (5 μg/mL human; 0.5 μg/mL mouse) or double (10 μg/mL human; 1.0 μg/mL mouse) dose of cisplatin, a single (1 μg/mL human; 0.05 μg/mL mouse) or double (2 μg/mL human; 0.01 μg/mL mouse) dose of doxorubicin or a combination of a single dose of both drugs together were compared to controls without drug exposure. Exposure to cisplatin or doxorubicin significantly decreased follicle health in human and mouse, supporting the suitability of the mouse as a model for the human ovary. There was also a significant reduction of mouse follicle number. Human ovarian stromal tissue exhibited increased apoptosis and decreased cell proliferation. Crucially, there was no evidence indicating the occurrence of multiplicative effects between cisplatin and doxorubicin.

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“…Consequently most prepubertal male patients who receive cancer treatment will achieve normal pubertal development . Further research continues to try and establish the mechanisms by which different treatments lead to damage …”

Section: Cancer and Fertilitymentioning

confidence: 99%

“…52,54,55 Further research continues to try and establish the mechanisms by which different treatments lead to damage. 56,57 Green et al, report that when compared with their siblings, survivors of childhood cancer were approximately half as likely to sire a pregnancy. 58 It remains unclear at present whether there is a longterm generational impact on the fertility of children born from male cancer survivors with a Danish study reporting no significant association 59 but potential mechanisms of effect have been identified in animal work.…”

Section: Disruption Of Hypothalamicpituitary-gonadal Axismentioning

confidence: 99%

Survival from cancer in young people: An overview of late effects focusing on reproductive health

Newton

Friend

Feltbower

et al. 2019

Acta Obstet Gynecol Scand

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This paper provides a summary of the areas of survival from childhood, teenage and young adult cancers and the significant late effects that can arise from treatment; with particular focus on the area of reproductive health and the impact on both fertility and pregnancy. To complete this review, Web of Science and MEDLINE were used. Search terms included: “"survival AND childhood OR teenage OR young adult cancer", "late effects", "childhood cancer", "teenage AND/OR young adult cancer", AND "fertility after cancer" OR "pregnancy AND cancer" OR "fertility preservation”. Additionally, the clinical expertise of the authors was drawn upon. Childhood cancer is a thankfully rare occurrence; however, the incidence is increasing. Survival rates remain high and this means that a growing population of childhood and young adult cancer survivors are reaching adulthood. For some of these adults, although cured of their cancer, they are now facing a future with lasting effects on their health from their treatments. These effects, commonly referred to as late effects, are defined as health problems related either directly to the underlying cancer or to its treatment and which occur months or years after treatment has finished. Reproductive health is an important consideration for these patients, and although many will be able to conceive naturally, some will exhibit impaired fertility after their treatments. This can include difficulties at all points along the path from conception to delivery of a live, healthy offspring. High‐quality, large‐population evidence is sparse in many areas relating to fertility risk from treatment and the maternal and fetal health of childhood cancer survivors. Yet given the potential for complications, the authors advocate consideration of fertility at the time of diagnosis and before potentially gonadotoxic treatment.

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Chemotherapy drugs cyclophosphamide, cisplatin and doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis

Cited by 71 publications

References 50 publications

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

Single and combined effects of cisplatin and doxorubicin on the human and mouse ovary in vitro

Survival from cancer in young people: An overview of late effects focusing on reproductive health

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