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MGH study finds female mammals produce
egg cells into adulthood
Finding refutes doctrine of a finite
supply of eggs, may have broad fertility implications
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BOSTON - March 10, 2004 - An underlying principle of female
reproductive biology appears to have been overturned by a report
from researchers at Massachusetts General Hospital (MGH). In an
article in the March 11, 2004 issue of Nature, the investigators
report that female mice retain the ability to make new egg cells
well into adulthood. It has been believed that most female mammals
are born with a finite supply of these cells, called oocytes, that
are lost at a steady rate until the supply is exhausted, leading
to menopause in women.
"If these findings hold up in humans, all theories about the
aging of the female reproductive system will have to be revisited,"
says Jonathan Tilly, PhD, of the Vincent
Center for Reproductive Biology at MGH, the paper's lead author.
"We also may need to revisit the mechanisms underlying such
environmental effects on fertility as smoking, chemotherapy and
radiation. Eventually this could lead to totally new approaches
to combating infertility in cancer patients and others." Tilly
is an associate professor of Obstetrics, Gynecology and Reproductive
Biology at Harvard Medical School.
For several years Tilly's group has been studying the mechanisms
behind the death of oocytes and follicles, the tiny sacs in which
the eggs grow. In both mice and humans, the vast majority of oocytes
are destined to die through a process called programmed cell death
or apoptosis, the body's natural way of eliminating unneeded or
damaged cells. The team's earlier research confirmed that oocytes
destroyed by chemotherapy drugs or radiation also die through
apoptosis, opening the possibility of designing ways to stop ovarian
damage in female cancer patients and perhaps to postpone normal
ovarian failure. However, to provide an essential context to their
efforts to inhibit oocyte apoptosis, the researchers decided to
measure the numbers of healthy and dying follicles in mouse ovaries
through the animals' lifespan.
What they found was remarkable. Measurements taken during the early
stages of life found a steady, low level of dying follicles, but
as the mice reached adulthood the number of dying follicles increased
markedly. In young adult animals, the researchers measured 1,200
dying follicles per ovary, compared with about 3,000 healthy follicles
remaining. Similarly elevated levels of dying follicles were measured
well into maturity. Although such a surprisingly high rate of follicle
loss would be expected to completely deplete a fixed population
of oocytes within a matter of days or weeks, female mice retain
healthy egg cells well past one year of age.
To make sure they were accurately measuring the rate at which follicles
were dying, the researchers evaluated whether dead and dying follicles
were being cleared from the ovaries. Their results confirmed that
the dying follicles were being cleared within three days of death
and thus represented a continuing level of cell death, not an accumulation
of "cellular corpses."
"Finding such a high level of follicle degeneration without
a corresponding reduction in the number of healthy follicles brought
us up against the dogma of a fixed supply of oocytes," Tilly
says. "The only probable interpretation was that the postnatal
ovary had to be retaining the ability to make new oocytes and follicles."
To investigate such a potentially revolutionary possibility, the
researchers ran several additional experiments.
- Careful examination of ovaries of young and mature mice identified
cells on the organs' outer surface that resembled germ cells,
which are the source of oocytes that develop in fetal animals.
These cells were found to express a gene known to be present only
in germ cells and were shown to maintain the ability to undergo
cell division in juvenile and adult ovaries.
- A key stage in the development of any germ cell is meiosis,
which results in egg or sperm cells with a single set of chromosomes
instead of the paired sets found in most cells. Finding a protein
that is only produced at the onset of meiosis in ovarian cells
of young and mature mice indicated that this aspect of oocyte
development continues after birth.
- Busulfan is a chemotherapy drug known to target proliferating
germ cells in males but have no effect on mature sperm cells.
Three weeks after being injected with busulfan, female mice were
found to have only 5 percent the supply of primordial (immature)
follicles than control mice had. The investigators went on to
show this difference was not due to increased death of primordial
follicles, implying that the busulfan-related drop in the number
of primordial follicles resulted from an absence of follicular
renewal.
- The researchers grafted ovarian tissue from normal adult mice
onto the ovaries of adult transgenic mice that express a green
marker protein in all of their cells. Several weeks later the
grafted ovaries in the transgenic mice were found to contain hybrid
follicles consisting of normal follicular cells surrounding green
oocytes. These results demonstrated that transgenic (green) germ
cells had migrated from the host ovary into the grafted ovarian
tissue and produced green oocytes, which formed new follicles
from the surrounding normal cells.
Tilly says that the concept of a fixed pool of oocytes, first asserted
almost a century ago, has been so widely accepted that he is not
aware of any studies over the past 50 years that have questioned
its accuracy. "The ovaries visibly lose healthy follicles throughout
life, while the testes continue to look the same. It was assumed
that the decline in total follicles represented the gradual disappearance
of a limited supply of oocytes. No one ever attempted to measure
the actual rate of oocyte or follicle death before because the dogma
was so persuasive," he explains.
Among many potential implications of the study is a different mechanism
underlying ovarian aging. It is known that eggs released by older
women are more likely to be abnormal, which has been attributed
to the eggs themselves being older. But the problems could instead
be the result of aging of the germline stem cells that produce the
oocytes. If these stem cells could be identified and isolated, a
whole new set of options for treating or preventing infertility
might open up.
"These are basic biological findings that may change everything
in our field," Tilly says. "Although there's no way to
say how long it may take for these findings to actually affect the
care of patients, we're very excited about the new set of scientific
questions we have to investigate."
Additional authors of the Nature study are co-first authors
Joshua Johnson, PhD, and Jacqueline Canning, along with Tomoko Kaneko,
MD, PhD, and James Pru, PhD, all of the Vincent Center for Reproductive
Biology. The study was supported by Vincent Memorial Research Funds
and the National
Institute on Aging.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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