How does chemotherapy treatment damage the prepubertal testis?

Abstract

Chemotherapy treatment is a mainstay of anticancer regimens, significantly contributing to the recent increase in childhood cancer survival rates. Conventional cancer therapy targets not only malignant but also healthy cells resulting in side effects including infertility. For prepubertal boys, there are currently no fertility preservation strategies in use, although several potential methods are under investigation. Most of the current knowledge in relation to prepubertal gonadotoxicity has been deduced from adult studies; however, the prepubertal testis is relatively quiescent in comparison to the adult. This review provides an overview of research to date in humans and animals describing chemotherapy-induced prepubertal gonadotoxicity, focusing on direct gonadal damage. Testicular damage is dependent upon the agent, dosage, administration schedule and age/pubertal status at time of treatment. The chemotherapy agents investigated so far target the germ cell population activating apoptotic pathways and may also impair Sertoli cell function. Due to use of combined chemotherapy agents for patients, the impact of individual drugs is hard to define, however, use of in vivo and in vitro animal models can overcome this problem. Furthering our understanding of how chemotherapy agents target the prepubertal testis will provide clarity to patients on the gonadotoxicity of different drugs and aid in the development of cytoprotective agents.

Testicular Function of Childhood Cancer Survivors: Who Is Worse?

“…Some centers have started to cryopreserve immature testicular tissue from pre-pubertal boys before starting chemotherapy treatment. In 2015, seven centers in Europe had already collected and stored more than 260 pre-pubertal testicular tissue samples, with biopsies undertaken only when treatment was deemed at high risk for later fertility complications [3]. It is not yet certain if such cryopreserved tissue can be successfully used later to restore fertility in humans.…”

“…The gonadotoxic potential of some treatments, such as alkylating agents and testicular irradiation, is well known [3]. Chemotherapy-induced testicular damage is drug-specific and dose-related: the extent of the damage and the speed of recovery depend on the agent used and the dose received.…”

“…Since adult testicular function is unpredictable, all boys already capable of ejaculating should, as a precaution, cryopreserve sperm before undergoing antineoplastic treatments. Pre-pubertal patients who do not yet have spermarche represent the category with major concerns about fertility, because the cryopreservation of testicular tissue with subsequently auto-graft is still an experimental procedure performed by few centers and with low probability of success [3].…”

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

“…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 …”

“…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.…”