The tiny translucent egg nestled in the special laboratory gel was a mere 30 days old, but its four-week birthday caused researchers to quietly celebrate. This was the first time anyone had successfully grown a woman's immature egg cells, contained in a tiny sac called a follicle, to a healthy and nearly mature egg in the laboratory. When an egg is fully mature, it is ready to be fertilized.
The researchers from Northwestern University Feinberg School of Medicine have completed the first critical step in the development of a new technique, which, if successful in the next steps, may eventually provide a new fertility option for women whose cancer treatments destroy their ability to reproduce.
The nearly mature follicles grown for 30 days in the laboratory had been plucked from ovarian tissue of cancer patients before they began chemotherapy and radiation treatments that would destroy their fertility. The cancer patients, from Northwestern Memorial Hospital, had agreed to participate in the experimental fertility study, which was funded by the National Institutes of Health.
"By being able to take an immature ovarian follicle and grow it to produce a good quality egg, we're closer to that holy grail, which is to get an egg directly from ovarian tissue that can be fertilized for a cancer patient," said Teresa Woodruff, chief of fertility preservation at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
"This represents the basic science breakthrough necessary to better accomplish our goals of fertility preservation in cancer patients in the future," added Woodruff, who developed the new technique with colleagues.
Woodruff is the senior author of a paper on the findings in the July 14 issue of the journal Human Reproduction.
The next step will be for Northwestern researchers to try to induce the egg's final division, called meiosis, so it sheds half of its DNA in order to be fertilized. The ultimate goal is for scientists to be able to freeze the immature follicles, then thaw and mature them in a culture to the point where they are ready to be fertilized.
"This is a very significant achievement because the early stage of the human ovarian follicle is really hard to grow in vitro. They're very fragile and delicate," said Min Xu, a paper coauthor and research assistant professor at the Feinberg School.
As the immature egg grew inside the follicle, it produced hormones just as it would inside a woman's body.
"That's a good sign that these follicles are healthy. The actual egg also is growing to the same size that we would see in an egg that a woman's body has ovulated," said Susan Barrett, a coauthor and post-doctoral fellow at the Feinberg School.
Women currently have few good options to save their ability to reproduce after cancer treatment. Men are able to freeze their sperm for later use before they begin fertility-destroying cancer therapies. The best option to preserve the fertility of a female cancer patient is to collect her eggs, fertilize them with sperm and freeze the resulting embryos. However, this option is often not a practical choice because it can delay cancer treatment, can't be performed on those who have not reached puberty, and requires fertilization -- a problem for those who do not have a male partner or do not wish to use donor sperm.
Other researchers have experimented with freezing entire ovaries or strips of ovarian tissue and implanting them in a woman's body once she is ready to have children. But for cancer patients, it is possible that cancer cells may be present in the ovarian tissue and result in a new cancer after the tissue is implanted. However, if follicles could be removed from the tissue and grown in the laboratory successfully, as this study suggests, then a new fertility preservation technique might become available for women who could not safely have an ovarian transplant.
The new Northwestern findings build on earlier research by the scientists, who grew mouse follicles in a culture, induced the eggs they contained to mature, fertilized them with mouse sperm and implanted them into female mice to establish pregnancy. The technique produced healthy, fertile generations of mice.
Woodruff, working with Lonnie Shea, professor of chemical and biological engineering at McCormick School of Engineering and Applied Science, achieved the new advance by suspending the human ovarian follicle in two different kinds of three-dimensional gels. Previous attempts to grow ovarian follicles had been on a flat surface, which the researchers now believe does not replicate conditions inside the body. These earlier attempts failed to develop good quality eggs that were healthy enough for fertilization.
Woodruff said the research also is significant because it is the first time scientists have been able to isolate and study a functioning individual human ovarian follicle.
"Because you don't take an ovary out of young women, we've never before been able to look inside the follicle of the human and ask how does it work, how do hormones change, how does the estrogen change in the follicle?" explained Woodruff, who also is the Thomas J. Watkins Professor of Obstetrics and Gynecology. "We never knew how an individual follicle regulated these hormones. This paper for the first time shows these individual hormones being regulated by one growing follicle."
The discovery, Woodruff said, will enable researchers to understand how nurse cells (granulosa cells), the cells that support and surround the maturing egg, communicate with the egg. "They provide a lot of information that the egg needs to grow and develop properly," Woodruff said. "It's a big priority for us to understand how the nurse cells talk to the egg." The information, she said, will help scientists understand how eggs grow and develop properly.
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