Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations.
This study assessed reproductive performance, fetal viability and teratogenicity in female mice exposed to cyclophosphamide across a timeline corresponding to different stages of follicle maturation. Pregnancies were established in female Balb/c mice 1-4 weeks after administration of a non-sterilizing dose of cyclophosphamide (75 mg/kg). Each mating group represented a different stage of follicular growth at the time of cyclophosphamide exposure. The number of corpora lutea, pregnancies and fetal resorptions were determined. Surviving fetuses were evaluated for gross malformations. Results indicated that conceptions attributable to follicles exposed to cyclophosphamide at a mature stage had a significantly lower number of implantation sites, 4.82 +/- 1.01 versus 8.27 +/- 0.81 in controls (P = 0.001) and a high resorption rate, 56% +/- 0.11 versus 34% +/- 0.07 in controls (P = 0.05). The proportion of corpora lutea in this group which resulted in viable fetuses was extremely low, 0.2 +/- 0.06 versus 0.51 +/- 0.07 in controls (P = 0.001). Malformation rate was more than 10 times higher in all treated groups (P < 0.05) and a particularly high incidence of 33% (P = 0.0014) was observed in conceptions attributable to oocytes exposed to cyclophosphamide at the earliest stages of follicle growth. With an extended interval between exposure and mating the malformation rate gradually decreased towards normal values in the 12th week group. This study suggests that the effect of cyclophosphamide on female gametes and subsequently on future reproduction is influenced by the stage of oocyte maturation at the time of exposure. Early fertilization post-chemotherapy can result in a high rate of pregnancy failure and high malformation rate. This should be taken into account when considering the use of oocyte retrieval, IVF and embryo cryopreservation in patients currently undergoing chemotherapy.
Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tigva, Israel. meirow@md2.huji.ac.il
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D000015:Abnormalities, Multiple / Q000139:chemically induced*; D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D020567:Fetal Weight; D008098:Litter Size; D018811:Maternal Exposure; D051379:Mice; D008807:Mice, Inbred BALB C; D009153:Mutagens / Q000633:toxicity*; D006080:Ovarian Follicle / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D013997:Time Factors
D009153:Mutagens; D003520:Cyclophosphamide