Regenerative Potential of Spermatogenesis after Gonadotoxic Therapies - Male Germline Stem Cells Developmental and Regenerative Potential - page 192

results (Da Cunha et al. 1987 ) or show that other gonadotropin suppression protocols
protected spermatogenesis in mice (Crawford et al. 1998 ; Kangasniemi et al. 1996a ;
Nonomura et al. 1991 ) (Table 9.3 ). However, recently, we have been able to demon-
strate that treatment with a GnRH antagonist and an antiandrogen starting immedi-
ately after irradiation significantly enhanced the ability of surviving stem spermatogonia
to produce differentiated germ cells (Wang et al. 2010). Hormonal suppressive treat-
ments for up to 11 weeks resulted in about a twofold increase in the percentage of
seminiferous tubules containing differentiated germ cells. Hormonal suppressive
treatment for 10 weeks after irradiation also resulted in a twofold increase in epididy-
mal sperm numbers about 20-30 weeks later and an increase in the percentage of
fertile males from 7 to 80%.
In contrast to the scant positive results and modest effect in the mouse, numerous
reports demonstrated that hormone suppression prior to and during radiation, pro-
carbazine, doxorubicin, indenopyridine, or heat treatments, markedly enhanced the
subsequent recovery of spermatogenesis and fertility (Delic et al. 1986a ; Hild et al.
2001 ; Jegou et al. 1991 ; Kangasniemi et al. 1995 ; Manabe et al. 1997 ; Morris and
Shalet 1990 ; Parchuri et al. 1993 ; Setchell et al. 2002 ; Weissenberg et al. 1995 ).
Note that in none of these studies was the protection of the survival of stem sper-
matogonia directly assessed. We proposed that the mechanism by which hormone
suppression enhances the subsequent recovery of spermatogenesis is by prevention
of the pronounced block in differentiation of surviving stem spermatogonia in rat
testes after exposure to cytotoxic agents (Meistrich et al. 2000 ).
Accordingly, when the hormone suppression was administered to the rats only
after irradiation, the differentiation of stem spermatogonia, which would have been
otherwise blocked, was restored (Meistrich and Kangasniemi 1997 ; Shuttlesworth
et al. 2000 ). Similar stimulation of recovery following procarbazine (Meistrich et al.
1999 ), busulfan (Udagawa et al. 2001 ), heat (Setchell et al. 2001 ) or hexanedione
(Blanchard et al. 1998 ) treatment has been observed. This hormone suppression-
stimulated spermatogonial differentiation led, after subsequent restoration of hor-
mone levels, to increased sperm counts and fertility (Meistrich et al. 2001 ).
Studies using hormone suppression in monkeys have not convincingly demon-
strated enhanced recovery of spermatogenesis following gonadotoxic injury.
Although one preliminary report based on a total of only three baboons suggested
that hormone suppression might decrease the gonadal damage from cyclophosph-
amide (Lewis et al. 1985 ), two larger studies using an adequate number of macaques
showed neither protection (Kamischke et al. 2003 ) nor stimulation (Boekelheide
et al. 2005 ) of recovery of spermatogenesis from radiation damage by hormone
treatment.
Seven clinical trials have been performed in attempts to demonstrate improvement
in the recovery of spermatogenesis in human males by hormone suppression treat-
ment before and during cytotoxic therapy (Brennemann et al. 1994 ; Fossa et al.
1988 ; Johnson et al. 1985 ; Kreuser et al. 1990 ; Masala et al. 1997 ; Redman and
Bajorunas 1987 ; Waxman et al. 1987 ). Only one of these studies showed that hor-
mone-suppression preserved subsequent sperm production of men, who received
cyclophosphamide in this case (Masala et al. 1997 ), but this study has not been