Teska Schuurman1, Ji-Ying Song2, Vera Wolters1, Marieke van de Ven3, Nienke van Trommel1, Ina Beerendonk4, Frédéric Amant1,5, Christianne Lok6. 1. Department of Gynecologic Oncology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek, Amsterdam, The Netherlands. 2. Department of Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 3. Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands. 5. Department of Gynecologic Oncology, UZ Leuven, Leuven, Belgium. 6. Department of Gynecologic Oncology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek, Amsterdam, The Netherlands. c.lok@nki.nl.
Abstract
PURPOSE: It is unknown if future fertility is compromised by the administration of chemotherapy during pregnancy. The aim of this study was to identify if chemotherapy affects the maternal ovaries during pregnancy and whether these effects depend on type of chemotherapy and duration of exposure. METHODS: Pregnant 8-week-old female BL6 mice were exposed to 6 different single chemotherapeutic agents (carboplatin, cisplatin, paclitaxel, epirubicin, doxorubicin, or cyclophosphamide) or saline at gestational day (GD) 13.5. The mice were sacrificed at GD 15.5 or GD 18.5. Ovaries were assessed by histopathology and immunohistochemistry. Follicle count was determined per follicle stage and per treatment modality. RESULTS: Maternal ovarian damage was demonstrated by the presence of apoptosis and necrosis in preantral follicles. The extent of this damage depends upon type of chemotherapy and duration of exposure (2 or 5 days). After short exposure, 81% of ovaries showed histopathologic signs of damage compared to 36% after long exposure, which might suggest a transient effect. Loss of primordial follicles (PMFs) was observed after both short and long exposure, with a reduction of more than 70%. Evidence of DNA damage, as demonstrated by phospho-H2AX expression, was present in 23% (range 0-89%) of PMFs exposed to chemotherapy, but only in the short exposure group. Overall, the least damage was seen after administration of paclitaxel. CONCLUSION: Despite physiological ovarian function suppression during gestation, chemotherapy-induced damage of the ovaries occurs in pregnant mouse models, potentially affecting future fertility.
PURPOSE: It is unknown if future fertility is compromised by the administration of chemotherapy during pregnancy. The aim of this study was to identify if chemotherapy affects the maternal ovaries during pregnancy and whether these effects depend on type of chemotherapy and duration of exposure. METHODS: Pregnant 8-week-old female BL6 mice were exposed to 6 different single chemotherapeutic agents (carboplatin, cisplatin, paclitaxel, epirubicin, doxorubicin, or cyclophosphamide) or saline at gestational day (GD) 13.5. The mice were sacrificed at GD 15.5 or GD 18.5. Ovaries were assessed by histopathology and immunohistochemistry. Follicle count was determined per follicle stage and per treatment modality. RESULTS: Maternal ovarian damage was demonstrated by the presence of apoptosis and necrosis in preantral follicles. The extent of this damage depends upon type of chemotherapy and duration of exposure (2 or 5 days). After short exposure, 81% of ovaries showed histopathologic signs of damage compared to 36% after long exposure, which might suggest a transient effect. Loss of primordial follicles (PMFs) was observed after both short and long exposure, with a reduction of more than 70%. Evidence of DNA damage, as demonstrated by phospho-H2AX expression, was present in 23% (range 0-89%) of PMFs exposed to chemotherapy, but only in the short exposure group. Overall, the least damage was seen after administration of paclitaxel. CONCLUSION: Despite physiological ovarian function suppression during gestation, chemotherapy-induced damage of the ovaries occurs in pregnant mouse models, potentially affecting future fertility.
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