Targeted
antiapoptotic agents for ovarian protection on chemotherapeutic agent-induced
ovarian toxicity
Chi-Huang Chen1,
Chia-Woei Wang1, Ming-I Hsu2, Chii-Ruey Tzeng1
Center for Reproductive Medicine & Sciences, Taipei Medical University
Hospital, Taiwan1, Department of Obstetrics & Gynecology, Wan
Fang Hospital,Taipei Medical University, Taiwan2
Introduction
Gonadotoxicity
after alkylating
agent is a well known complication. We aim to investigate the protective effect of S1P,
an apoptosis-inhibitor, on chemotherapy-induced ovarian toxicity.
Design:
Animal study
Material & Methods
Twelve 8-week
old female FVB/NJNarl mice were randomly divided into four groups: control (n=3),
busulfan (B, n=3), low concentration of S1P plus busulfan (S1PL + B, n=3) and
high concentration of S1P plus busulfan (S1PH + B). In the S1P + B group, 0.5
mM of S1P, prepared in a vehicle (PET), was injected into the bursa of one
ovary (S1PL + B group, n=3), and 2.0 mM of S1P in PET was injected into the
bursa of the contralateral ovary as the S1PH + B group (n=3). Only PET was
injected into the bursa of both ovaries in the B (n=3) and control groups
(n=3). One hour later, mice in the B and S1P + B groups were injected with
busulfan intraperitoneally at a dose of 36 mg/kg. After 4 weeks, all mice were
evaluated the whole ovaries of follicle number by H&E stain, expression of
AMH and GDF-9 by RT-PCR. Immunohistochemistry of
Caspase-3 assayed for the ovarian apoptosis
24 and 72 hours after busulfan treatment was compared the difference.
Results
Obvious
destruction of ovarian structure, significant depletion of follicles and the decreased
lowest levels of AMH and GDF-9 were demonstrated in the group B among the four groups
(p < 0.01). Mice pretreated with S1P (S1PL + B group or S1PH + B
group) revealed lower follicle counts and levels of AMH and GDF-9 than that of
the control group (p<0.01). Active
fragments of caspase-3 showed much more in busulfan-treated group than that of other
three groups.
Conclusions
S1P is an ovarian protective agent that prevents chemotherapy-induced
gonadotoxicity. Immunohistochemistry of caspase-3 evidences the significant ovarian
toxicity after busulfan treatment without S1P protection. The follicle counts and levels of AMH and
GDF-9 are direct and reliable parameters for evaluating the ovarian reserve,
and potentially utilized as markers to assess female fertility and detect the
impact of chemotherapy. We suggest that S1P pretreatment is a promising option
for fertility preservation.
Supported by:
NSC99-2314-B-016-013-MY3, Taiwan, ROC
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