Hum. Reprod. Advance Access published online on February 12, 2004
Human Reproduction, doi:10.1093/humrep/deh120
© 2004 by European Society of Human Reproduction and Embryology
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1 Center for Fertility and Reproductive Endocrinology, Virginia Mason Medical Center, Seattle, Washington, USA
* To whom correspondence should be addressed. E-mail: obsgsl{at}vmmc.org.
BACKGROUND: Gonadal failure secondary to alkylating agents may be related to ovulatory status. The objective of this investigation was to evaluate whether anovulation protected ovarian follicles during treatment with cyclophosphamide. METHODS: Four groups (n = 20 mature female Sprague-Dawley rats per group) were studied: control (group I), 5 mg/kg/day cyclophosphamide only (group II), 5 mg/kg/day cyclophosphamide and the combination of 50 µg ethinyl estradiol/2 mg norgestrel (group III) and 5 mg/kg/day cyclophosphamide and 2.5 µg leuprolide acetate daily (group IV). Animals were sacrificed after 4 weeks of treatment. Follicles were classified as medium (300-450 µm) and large (>450 µm) per section of ovary. RESULTS: Group II developed a significantly greater number of medium and large follicles [15.1 ± 6.1 and 4.9 ± 1.9 (mean ± SD), respectively] compared with group I [7.1 ± 2.1 and 1.0 ± 0.7 (mean ± SD), respectively] (P Key words:
Key words: chemotherapy/cyclophosphamide/cytotoxic therapy/oocyte apoptosis/ovarian failure
Revised October 29, 2003
Accepted November 10, 2003
Article
Anovulation in the prevention of cytotoxic-induced follicular attrition and ovarian failure
Abstract 
0.05). Groups III and IV developed a significantly greater number of medium follicles [13.2 ± 2.5 and 10.8 ± 2.3 (mean ± SD), respectively) compared with group I (P 0.05). There was a trend toward a greater number of large follicles in groups III and IV when they were compared with group I. There were no differences in medium follicles in groups II, III and IV. No differences were noted in the number of large follicles between groups III and IV (2.9 ± 1.2 and 2.3 ± 1.0, respectively). CONCLUSIONS: These results suggest that in the rat model, cyclophosphamide exerts a stimulatory effect on the ovary resulting in the greater development of both medium and large follicles. Anovulation conferred no protection against cyclophosphamide-induced gonadal toxicity. These data suggest that in the rat model, cyclophosphamide may result in ovarian failure by enhancing recruitment of follicles regardless of ovulatory status or hormonal milieu.
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