Contrary to long-held scientific views that the number of oocytes (eggs) in the ovaries of most mammals is fixed at birth, scientists report that new oocyte-containing follicles continue to develop in the ovaries of adult mice. The research suggests that these new oocytes come from stem cells located in the ovary. The study, supported by the National Institute on Aging (NIA), one of the National Institutes of Health, was conducted by Jonathan L. Tilly, Ph.D., and colleagues at Massachusetts General Hospital and Harvard Medical School and appears in the March 11, 2004, issue of Nature* .
"If this finding is confirmed by others, Dr. Tilly and his colleagues would seem to have rewritten the book on reproductive biology--at least for mice," says Frank Bellino, Ph.D., Deputy Associate Director of the Biology of Aging Program at the NIA. "Further study about how oocyte production in adults is controlled might eventually make it possible to regulate the rate at which oocytes are formed in women. This, in turn, could possibly be used to delay premature ovarian failure as well as menopause and may help women maintain their health for a longer period of time."
Tilly's group began by comparing the numbers of healthy and degenerating follicles in the ovaries of a particular strain of mice from birth through young adulthood. They reasoned that if the number of follicles in the ovary is set at or shortly after birth, then the loss of healthy follicles over time would be accounted for by the total number of follicles undergoing atresia (degeneration) during the same time period. Instead, they found that the incidence of atretic follicles was significantly greater than the loss over time of healthy or non-atretic follicles. Evidence that degenerating follicles disappeared from the ovaries within 3 days (and, thus, were not being counted more than once) suggested to the investigators that the ovaries continue to produce new oocyte-containing follicles into adulthood.
Further studies showed the same results in two other strains of mice. In fact, in one strain (AKR), the number of ovarian follicles actually increased with age from birth to young adulthood, despite marked atresia (degeneration). The scientists went on to identify the presence of large cells on the surface layer of cells in the mouse ovaries that they proved to be germ cells (stem cells that are precursors to oocytes and are not associated with follicles). They also found signs in adult animals of meiosis, the specialized cell division that only occurs in the formation of sex cells, which, according to traditional thinking, should have stopped before birth.
Lastly, the investigators transplanted ovarian tissue from adult wild-type mice into adult female mice developed to express a particular type of protein, called green fluorescent protein (GFP), in all cells throughout their bodies. When later examined microscopically, the transplanted ovarian tissue contained wild-type follicles housing GFP-positive oocytes, indicative of new follicle production in adult ovaries.
Just as experts who once believed that neurons in the human brain did not regenerate have recently learned that in a few brain regions, new neurons can be born, even in the old brain, as early as 1921, scientists believed that no new oocytes were made after the ovary of any mammal, including a woman, was formed. Then, according to Dr. Tilly, "this concept was solidified as dogma in 1951 in a paper** that critically evaluated, and effectively dispelled, any work contrary to (this) belief….The present study provides evidence that challenge the validity of this belief, which represents one of the most basic underpinnings of reproductive biology."
The research was also supported by Vincent Memorial Research Funds.
The NIA is one of 27 Institutes and Centers that constitute the National Institutes of Health (NIH). The NIA leads Federal efforts to support and conduct basic, clinical, epidemiological, and social research on aging and the special needs of older people. Press releases, brochures, and other materials about aging and aging research can be viewed at the NIA website, http://www.nia.nih.gov.
*J Johnson, J Canning, T Kaneko, JK Pru, and JL Tilly, "Germline stem cells and follicular renewal in the postnatal mammalian ovary," Nature, Vol. 428, No. 6979, pp. 145-150. **Zuckerman, S. "The number of oocytes in the mature ovary." Recent Progress in Hormone Research. Vol. 6, pp. 63-108 (1951).
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