BackgroundYoung cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries.MethodsFemale mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin.ResultsA single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment.ConclusionsOur results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.

HighlightsOf 310 brain tumors patients recruited, histology of 99 lesions was available.Of those, 5 were histologically confirmed as radiation-induced malformations.TRAMs cannot differentiate active tumor from vascular malformation.

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Introduction: Advances in cancer therapy have improved the long-term survival of cancer patients who may then face infertility and premature gonadal failure due to chemotherapy. It has been demonstrated that the chemotherapeutic agent doxorubicin (DXR) induces apoptosis in germ cells, though its role in inflicting potential gonadal failure remains obscure. We had previously shown ovarian damage in mice following DXR treatment, manifested by reduced ovarian size and weight and by apoptosis. We aimed at establishing a real-time in vivo molecular imaging platform in mice designated to evaluate chemotherapy-induced toxicity and to assess potential vascular insult in both ovaries and testes. Methods: The volume of both ovaries and testes was measured in vivo by ultrasound biomicroscopy (Vevo2100) and by high resolution MRI, over a period of one month after adminstration of 10mg/kg intraperitoneal DXR. Ovaries were imaged by ultrasound using microbubbles as a contrast agent for evaluating the effect of DXR on ovarian blood flow. Results: We have established a platform of visualizing the gonads by innovative high resolution ultrasound biomicroscopy and MRI that enabled in vivo detection of chemotherapy-induced effects in the same individuals over time. We observed a constant, significant reduction in gonadal volume, evident by both MRI and ultrasound. The ovary volume was reduced to 52% (N=10, p<0.05) of baseline values over one month. A similar trend was observed in the testes (reduced to 38% of baseline values over one month; N=6 p<0.05)). The use of bubbles as contrast media depicted a 30% reduction in ovarian blood flow already 15 min after DXR administration. Conclusions: Using high resolution, state of the art imaging modules enabled us to trace chemotherapy-induce gonadotoxicity by in vivo imaging of the same individuals throughout an extended period of time. The acute reduction of ovarian blood flow following chemotherapy treatment may suggest a role for vascular injury in inflicting ovarian damage. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A229.