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.

Figure 1

PRISMA flow diagram of literature search. PRISMA flow diagram of search results, study screening, and study inclusion, following a review of the literature carried out using PRISMA guidelines (Moher et al. 2009).

Figure 2

Comparison of testicular development in humans and rodents. (A) Relative timeframe of important developmental processes taking place between foetal development and puberty in humans (Chemes 2001) and the mouse model (Vergouwen et al. 1993). Solid line indicates no activity of the cells at the relevant time points and dashed line represents the unknown nature of Leydig cell development during this timeframe. (B) Comparison of the histology of the testis throughout development in the human, from foetal development through to the adult testis. dpc, days post coitum; GW, gestational week; pnd, postnatal day.