Ovarian failure and infertility are common side effects for women who undergo radiation and chemotherapy. In most mammals, the female's entire supply of oocytes is created during embryonic development, and as many as 80 percent of the oocytes die before birth. Oocytes that remain are extremely sensitive to agents used in cancer treatment, which trigger programmed cell death, a process known as apoptosis.
"Unfortunately, there are no pharmacological or other therapies to prevent this catastrophic problem," said Richard Kolesnick, M.D., head of MSKCC's Laboratory of Signal Transduction, and a lead author of the study.
Zvi Fuks, M.D., a collaborator and an expert on radiation effects, explained that women, from birth to menopause, are likely to become sterile if the ovaries are exposed to radiation during treatment for cancer.
Apoptosis begins in oocytes when a lipid termed ceramide is produced in response to radiation or drugs. S1P works by blocking ceramide action - the oocytes never receive the signal to begin apoptosis.
Two months after treating the female mice with radiation, the researchers mated them with normal males. Surprisingly, S1P-treated mothers delivered normal litters, and the offspring appeared normal by several criteria. Further, subsequent generations also appeared normal. Nevertheless, the appearance of normality does not exclude the possibility of genetic damage that might be expressed in later generations.
"The ability to prevent sterility may not be desirable," Dr. Kolesnick says. The current concept of oocyte deletion after radiation or drug exposure suggests that organisms eliminate damaged oocytes to protect the genome of the offspring. "We had to ask ourselves, 'Are we now preserving the most damaged oocytes?' "
To address the question of whether there were genetic abnormalities in the irradiated mothers' oocytes, the researchers retrieved oocytes from the mothers treated with S1P and radiation, and found no significant damage.
Then they checked the progeny to see if any genetic damage had occurred, and similarly failed to find any abnormalities.
"What this research suggests," according to Dr. Kolesnick, "is that, when using an S1P-based pharmacological approach, it might be possible to one day preserve ovarian function without propagating genetic damage."
The discovery provides hope for women who undergo cancer treatments and want to preserve their fertility. "But," Dr. Fuks adds, "this is still translational research, and there is still much work to be done." Further research is being planned, he said.
Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital and Harvard Medical School, and Dr. Kolesnick were co-Principal Investigators for the study, which involved the efforts of scientists at Cornell University Medical College, the University of Maryland, and Case Western Reserve University, and two departments at MSKCC.
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Journal
Nature Medicine