The chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses, according to a study in mouse cells published in the open access journal BMC Cancer.
Norah Spears, the corresponding author 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, which are the cells that give rise to eggs. 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.
Norah Spears said: "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, called an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
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 the laboratory (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.
Norah 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 living organisms (in vivo).
Further research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damages 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.
Norah Spears said: "A woman's reproductive lifespan 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."
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Notes to editor:
1. Etoposide damages female germ cells in the developing ovary
Agnes Stefansdottir, Zoe C. Johnston, Nicola Powles-Glover, Richard A. Anderson, Ian R. Adams and Norah Spears
BMC Cancer 2016
DOI: 10.1186/s12885-016-2505-9
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