Abstract
The successful treatment of childhood cancer with chemotherapy and radiotherapy
may be associated with testicular damage resulting in impaired spermatogenesis and
temporary or permanent infertility in adulthood. In this study testicular function and
semen quality was investigated in 33 survivors of childhood cancer. Treatment of
childhood cancer was associated with a significant risk of impaired spermatogenesis,
with 30.3% of this population being azoospermic and 18.2% being oligozoospermic.
Moreover, in those men who do have surviving spermatogenesis after treatment, it is
commonly compromised, with reductions being observed in ejaculate volume, sperm
concentration, sperm motility and the proportion of morphologically normal sperm.
Only 33.3% of this group of 33 male childhood cancer survivors had completely
normal semen quality by conventional criteria. However, the sperm produced do not
appear to carry a greater burden of damaged DNA compared with the healthy
population, suggesting that assisted conception treatment is a safe option for these
men.
Detection of gonadal damage in the prepubertal male is hampered by lack of a
sensitive marker. The role of inhibin B as a marker of early gonadotoxic effects of
chemotherapy in prepubertal children treated for cancer was investigated. In
prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production
of inhibin B during and immediately after treatment stopped, although one boy
showed a delayed deleterious effect. Inhibin B changed earlier and appeared to be a
more sensitive marker of gonadal damage than FSH or LH. Prospective studies are underway combining inhibin B with FSH, LH and sex hormone measurements, to
assess the impact of cancer therapy on gonadal function in children, particularly as
they approach and progress through puberty.
For prepubertal boys fertility preservation through semen cryopreservation is not an
option and consequently, attention is focusing on the development of techniques that
might preserve or restore fertility potential in boys being subjected to gonadotoxic
cancer therapy. In rats, it has been shown that some germ cells survive cytotoxic
therapy and that the resulting azoospermia is a consequence of the inability of those
spermatogonia that are present to proliferate and differentiate. Suppression of the
hypothalamic-pituitary-gonadal (H-P-G) axis facilitates recovery of spermatogenesis
following such cytotoxic treatment. Investigation of whether suppression of the H-PG
axis in men rendered azoospermic by treatment for childhood cancer might restore
spermatogenesis was undertaken, using both semen analysis and testicular biopsy as
end points. In men treated with sterilising radiotherapy and chemotherapy for
childhood cancer, effective gonadotrophin suppression with medroxyprogesterone
acetate for at least 3 months did not result in restoration of spermatogenesis. The
absence of histological evidence of spermatogonial stem cells in testicular biopsies
from these men before and after suppression suggests complete ablation of the
germinal epithelium and irreversible infertility.
Understanding the vulnerability of the prepubertal human testis to cytotoxic damage
is compounded by the dearth of data describing normal testicular development in the prepubertal human. Based on immunohistochemical studies in marmosets, a primate that exhibits a similar developmental profile to the human male, it has been shown
that significant testicular development occurs during childhood long before the
clinical onset of puberty. If we can establish that cell activity does occur in the
'quiescent' testis in boys and is comparable to changes shown in the marmoset, it
will validate use of the marmoset as a model for the human in this instance and give
encouragement to the possibility of using this primate model to develop a method of
protecting spermatogenesis in boys undergoing cancer therapy prior to puberty.
Preliminary studies to investigate the development of the prepubertal human testis
confirmed testicular cell activity in the foetal and neonatal periods and infancy
comparable to that shown in the marmoset. However, to date development during
mid childhood and early puberty has proved to be somewhat discordant with the
marmoset studies. It is too premature to definitively conclude that marmoset and
human testicular development are dissimilar, as a number of explanations have been
proffered to explain the discrepancies, including suboptimal tissue fixation and
antigen preservation in the human tissues.
