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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.
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.
"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
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
"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.
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.