Biomedical Engineering Reference
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subsequently replicated. The one attempt to restore spermatogenesis by hormone
suppression after cytotoxic therapy was also unsuccessful (Thomson et al.
2002
).
However, it should be noted that there were shortcomings in the clinical studies that
may have masked subtle effects. The use of testosterone or medroxyprogesterone
either alone (Fossa et al.
1988
; Redman and Bajorunas
1987
; Thomson et al.
2002
)
or combined with a GnRH analogue (Waxman et al.
1987
) is suboptimal given that,
in animal studies, both of these steroids reduce the stimulatory effects of GnRH
analogs on the recovery of spermatogenesis after cytotoxic damage (Shetty et al.
2002, 2004
). Some treatment regimens were not sufficiently gonadotoxic to cause
prolonged sterility (Brennemann et al.
1994
; Kreuser et al.
1990
); conversely some
regimens may have delivered doses well above those that would ablate all sper-
matogonial stem cells, since no evidence of spermatogenesis was observed in
almost all patients even after many years (Johnson et al.
1985
; Thomson et al.
2002
;
Waxman et al.
1987
).
9.7
Analysis of Interspecies Differences
The above data indicated the many similarities in the effects of gonadotoxic effects
in the four different species considered. In all cases, the somatic cells are highly
resistant to killing by the cytotoxic agents; the later stage germ cells are also rela-
tively resistant to killing; the differentiating spermatogonia are most sensitive; and
the stem cells have intermediate sensitivity. The time courses of depletion of sperm
production are proportional because the surviving post-spermatogonial cells dif-
ferentiate with kinetics determined by the cycle of the seminiferous epithelium, and
then sperm count is reduced at the time when the sensitive differentiated sper-
matogonia would have produced sperm. Also the stem cells are highly sensitive to
radiation and the alkylating agents procarbazine, busulfan, and chlorambucil, and
relatively resistant to topoisomerase inhibitors, antimetabolites, and microtubule
inhibitors. In all species, there is some evidence for progressive loss of putative
stem type A spermatogonia for several months after the toxic insult, and this affects
sperm production in primates but not in mice.
The differences between species occur with respect to the survival of the stem
cells, regeneration of their numbers, and recovery of spermatogenesis from the
surviving stem cells.
Killing of putative stem spermatogonia by radiation, as assessed by histological
counts of cells, was similar in mice and rats, but the stem cells in monkeys and
human were more sensitive than those in rodents as indicated by reductions in
spermatogonial counts occurring at lower doses of radiation (Table
9.1
). The rea-
sons for these differences in sensitivity are not known. Whereas the spermatogonial
stem cells of the rodents are almost exclusively in the A
s
and to a limited extent in
the A
pr
populations, less is known about the distribution of stem cells among the
spermatogonial subtypes in primates. The stem cells in primates appear to be limited
to the A
dark
and A
pale
spermatogonia, which have a molecular phenotype corresponding
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