Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy?

Background: Inexplicably, boys treated with some therapies for cancer at age 2-10 years, a time of supposed 'testicular quiescence', are at risk of low sperm counts/infertility in adulthood. Our aims were to use the marmoset as a surrogate for man to establish testicular cell function/activity during 'quiescence' between the neonatal period and puberty, and to test if any cell activity could be suppressed by prior treatment with a GnRH antagonist.

Methods And Results: Based on immunoexpression studies, functional development of Sertoli cells (SGP-2, androgen receptor) and Leydig cells (3 beta-hydroxysteroid dehydrogenase) was detectable at an age (35 weeks) when the testis is considered to be quiescent, and in advance of the pubertal rise in blood testosterone levels (50-60 weeks). Other changes at 35 weeks were the appearance of focal seminiferous tubule lumens and proliferating germ cells [indicated by immunoexpression of proliferating cell nuclear antigen (PCNA)]. Treatment from 25 to 35 weeks with GnRH antagonist largely (>85%) prevented these changes. However, the PCNA-labelling index of spermatogonia in GnRH antagonist-treated animals did not differ from controls (41.3 versus 43.6%) though total spermatogonia volume per testis was reduced by 41%. Some protein markers (inhibin-alpha, estrogen receptor-beta) showed little change with age or treatment. Beyond 35 weeks, GnRH antagonist-treated animals showed a delay in the pubertal rise in plasma testosterone levels.

Conclusions: These findings reinforce the view that the 'childhood' testis is not quiescent. This may explain the damaging effects of some cancer therapies on subsequent fertility of boys and raises the issue of protective intervention. The present studies suggest that GnRH antagonist-based intervention might be only partially successful. Identification of the factors regulating spermatogonial development in the infant marmoset may aid in the design of such strategies.