Preclinical Study Finds Etoposide May Damage Developing Ovaries of Female Fetuses
The chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses, according to a preclinical study of mouse cells published by Stefansdottir et al in BMC Cancer.
Norah Spears, DPhil, the corresponding study author and Professor of Reproductive Physiology at the University of Edinburgh, said, “In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb. The drug affects the germ cells in the ovaries.… This is important because it could mean that the fertility of the offspring could be affected in later life.”
Etoposide is considered safe for women in the second and third trimesters of pregnancy. However, information on the long-term effects of chemotherapy treatment on the future fertility of female fetuses exposed to chemotherapy is limited.
Dr. Spears continued, “This study suggests that chemotherapy treatment may have important longer-term effects on the babies of women who undergo chemotherapy while pregnant, which would only become apparent in adulthood. This is an issue that has not been explored until now. Studies looking at the effects of taking chemotherapy drugs during pregnancy have focused on the immediate effects, such as increased miscarriage rates or severe fetal abnormalities.”
Ovarian follicles are the basic units of the female reproductive system, each containing an immature egg cell, or oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Key Findings
The researchers found that exposure of mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in vitro. They then exposed groups of six ovaries each to different doses of etoposide. The doses were considered low relative to those normally administered to patients undergoing chemotherapy.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively. In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
Study Implications
Dr. Spears added, “Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy.”
The researchers caution that despite of the value of in vitro methods like the one used in this study for preliminary screening, effects observed in vitro may not necessarily be observable in vivo.
Further research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA, or because etoposide affects other processes such as transcription, and to see whether the adverse effects of etoposide in germ cells are also found in human cases.
Dr. Spears concluded, “A woman's reproductive life span is determined before birth, while the ovaries are developing in the womb. The second trimester of pregnancy is particularly important as this is when female germ cells form follicles which will determine how many eggs a woman will be able to release in her lifetime. If the results we have seen in these mouse studies are found to be replicated in humans, some of that germ cell supply would be lost, which could later result in early menopause, thus reducing the woman's fertility window.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
