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Vol. LVIII, No. 18
September 8, 2006
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New Technique May Offer Fertility-Sparing Option to Cancer Survivors

On the front page...

Researchers funded by NICHD have developed a new technique that may provide a fertility-sparing option for women with cancer and other women at risk of infertility.

Although males can store sperm at a sperm bank, no comparable option exists for women. A woman's eggs seldom survive the freezing and subsequent thawing that stored sperm undergoes prior to fertilization.

Continued...

The new technique, developed and tested in mice, involves culturing the tiny sac, or follicle, that gives rise to an egg cell, in a gelatin mixture derived from algae. After treatment with hormones, the follicle matures, releasing the egg which can then be fertilized and implanted in a female mouse, resulting in pregnancy and birth.

Unlike mature eggs, follicles can survive the freezing process, making them excellent candidates for long-term storage.

 
Dr. Louis De Paolo, chief of NICHD’s Reproductive Sciences Branch, is project officer for the study.  

"This achievement opens up a new realm of exciting possibilities, from preserving fertility for patients, to protecting endangered species," said NIH director Dr. Elias Zerhouni. "This interdisciplinary effort — between materials scientists and reproductive specialists — yielded a promising new technique that researchers from either field, if working alone, probably would not have developed."

Where earlier attempts had failed, the new technique succeeded because it involved injecting the follicle into the gelatin mixture, providing 3 dimensions of support for the developing follicle. The gelatin mixture was specially engineered to allow reproductive hormones and growth factors to reach the follicle.

In previous attempts, follicles were cultured on a flat surface. The 2-dimensional culture method and resulting lack of physical support for the follicles failed to yield eggs that could achieve fertilization.

The article describing the accomplishment was published online recently in the journal Tissue Engineering. The research was conducted by Dr. Teresa K. Woodruff and colleagues at the Center for Reproductive Research at Northwestern University. Materials scientist Dr. Lonnie Shea, also at Northwestern, designed the gelatin mixture to culture the follicles. The center is part of an NICHD program that promotes multidisciplinary interactions between basic and clinical scientists in the reproductive sciences.

Recent advances in cancer treatment have greatly improved survival rates for patients, explained the project officer for the study, Dr. Louis De Paolo, chief of NICHD's Reproductive Sciences Branch. According to one estimate, as of 2001, an estimated 10 million Americans had survived cancer. Unfortunately, however, radiation and chemotherapy used to treat cancer can damage reproductive tissues and leave survivors infertile.

"Right now, the only feasible option for women facing the prospect of infertility is in vitro fertilization and long-term storage of embryos," De Paolo said. "But this option is not suitable for women who have not yet decided whether they want to start a family."

With the new technique, a small section of the ovary could be removed and frozen for later use. Studies with both lab animals and human beings show that ovarian tissue containing follicles can be successfully frozen and revived.

 
Dr. Lonnie Shea and Dr. Teresa K. Woodruff of Northwestern University collaborated on the fertility study.  

If the technology is successfully adapted for human use, the frozen follicles could be thawed and then cultured in the gel at a time when a woman is ready to begin a family. The eggs that result from the culture could then be fertilized with the partner's sperm and implanted in the uterus to establish a pregnancy.

De Paolo noted that, as with any other advance, the technique needs to be confirmed by other researchers. He added that, at this point, a few technical barriers remain, but these can most probably be overcome. Human follicles are larger than mouse follicles and take longer to mature. Researchers would need to recalibrate the dose and duration of the hormones needed to foster the egg's release. They would also need to adjust the gelatin mix to accommodate the larger follicle size.

Currently, Woodruff and her colleagues are working to adapt the technique to human beings as well as to rhesus monkeys, cows, dogs and cats. The researchers hope to apply what they learn in monkeys and cows to their work with human ovarian tissue. The technique could also be used in breeding programs for laboratory monkeys and in cattle breeding, preserving reproductive tissues from a female with desired characteristics.

The work with dogs and cats, undertaken with the National Zoo in Washington, D.C., serves as a prototype for endangered species. The researchers hope to adapt the technique to preserve reproductive tissue from such rare animals as Siberian tigers and Mexican wolves.

In addition to cancer patients, De Paolo sees other women benefiting from the technology, such as women with reproductive disorders like endometriosis, which increases the risk for infertility.

Originally, the researchers began work on the technique so they could observe the process by which the egg matures. "What we hope to understand at a fundamental level is how follicles transition from various stages of development," Woodruff said.

However, such basic science observations may also have applications for the treatment of human infertility.

Currently, women undergoing fertility treatments must receive hormones that stimulate ovulation. With the new technique, ovarian tissue could be removed and the follicles could be placed in culture to mature. This would do away with the need for fertility patients to receive ovulation-inducing hormones.

The technique might also improve the odds that a successful pregnancy would result. When treating infertile couples, reproductive health specialists typically harvest several eggs and create many embryos. To increase the odds of establishing a successful pregnancy, doctors may implant more than one embryo into the uterus at the same time. Implanting more than one embryo may result in a pregnancy with twins or triplets. Such multiple pregnancies increase the chances of premature birth, which increases the risk of such life-long complications as mental retardation, learning disabilities, cerebral palsy and blindness.

Currently, most infertility clinics create a large number of embryos. Most of the embryos are placed in long-term storage. If pregnancy doesn't result after the first implantation attempt, then doctors can make more attempts. Often, several attempts may be needed to establish a pregnancy.

In preliminary observations, Woodruff has found that follicles differ in how they respond to the hormones that foster release of the egg. Some follicles appear to give rise to healthier eggs that have a greater chance of developing into an embryo than do eggs from other follicles. With the new technique, it may one day be possible to choose eggs that have the greatest chance of leading to a pregnancy. This might allow a pregnancy to be established by implanting only one embryo at a time, with only one or two attempts, doing away with the chances of establishing a multiple pregnancy. If the new method increased the chances that early implantation attempts could successfully establish a pregnancy, this would eliminate the need to create a large number of embryos for storage.

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