Just wonderin'....
Findings may hold clues to healthier menopause
By Richard A. Knox, Globe Staff, 02/01/99
Boston scientists have abolished the mouse version of menopause, opening a new window on the mechanisms of female aging.
The researchers reported today that they have engineered mice whose ovaries grow viable eggs and secrete estrogen into advanced old age - the mouse equivalent of human centenarians.
Dr. Jonathan L. Tilly of Massachusetts General Hospital, who led the project, said his team is nowhere near trying the same thing in humans and isn't sure whether that would even be a good thing. But the genetically engineered mice offer ways to study what happens to female blood vessels, bones, brain cells, and other tissues when one of the normal mainsprings of aging is suspended indefinitely.
''To extend ovarian life span is unbelievable,'' Tilly said in an
interview. ''With sustained ovary function, we would expect various organ
systems to benefit, and overall life span to be extended.''
The new mouse strain does not open the door to geriatric motherhood, possibly because the aged animals lack the pituitary hormones necessary to sustain pregnancy.
However, Tilly and his colleagues hope their findings will lead to treatments to preserve fertility in women who undergo premature menopause due to an inborn disease or cancer chemotherapy.
The researchers' main aim is to better understand menopause-driven disorders so scientists can devise treatments to benefit menopausal women. For instance, the ovaries secrete other substances besides estrogen that might affect aging.
''This provides us with a model that will allow us to tease out the
molecular and cellular mechanisms of menopause, and beyond that, the
mechanisms that link menopause to the diseases of aging in women,'' added
Dr. Frank Bellino of the National Institute on Aging, which partially
funded the research.
Dr. Wulf Utian of Case Western Reserve Medical School in Cleveland, a leading menopause specialist, said the mouse strain could help solve such enigmas as why some middle-age women have youthful-appearing ovaries while those of others at the same age are shriveled.
''This work has opened new vistas, but the end of the rainbow is still
far away,'' Utian said in an interview.
The mouse experiments are reported in the current issue of Nature Genetics. They were carried out by Tilly and his colleagues at the Vincent Center for Reproductive Biology at MGH along with Stanley J. Korsmeyer of Dana Farber Cancer Center and co-workers at Washington University in St. Louis and the University of Maryland.
The group was able to arrest what had seemed an immutable law of mammalian nature, the inexorable depletion of ova or egg cells. Ovaries in all mammals obey a strict genetic command that causes ova to die at a steady rate throughout life until the supply is depleted.
The ovaries of human fetuses contain several million eggs, but for unknown reasons the number dwindles to about 1 million at the time of birth. At puberty, girls have about 400,000 egg cells, but by menopause (age 51 on average), nearly none remain, even though only one ovum is normally released from the ovary each month during the 450 or so menstrual cycles a normal woman will have.
Because ova are the females' main source of estrogen, their exhaustion starts a chain of events linked to diseases as diverse as osteoporosis and dementia.
The MGH researcher said he doesn't ''want anyone to think this will have immediate application in humans.''
''This is the first time anyone has proved this can work, and if it can
work in a mouse, perhaps it will in humans,'' he said. ''Now we can ask
the question for the first time: Do we even want to sustain ovarian
function? We couldn't test that before.''
One potential problem is that perpetual estrogen output could raise the risk of cancer, just as current postmenopausal estrogen supplements do for uterine cancer and possibly for breast cancer. So far, the researchers have seen no cancers in their aged mice, but relatively few animals have been studied.
Indications are that the geriatric mice maintain a strikingly youthful character without evidence of harmful estrogen-related effects. Their uteruses resemble those of much younger animals instead of the shrunken organs of normal aged mice.
The researchers were surprised to find that all it took to forestall the normal aging of ovaries was to disable a single master gene that controls the rate of cell death.
The gene, called bax, controls the rate of programmed cell death, a self-destruct mechanism scientifically known as apoptosis that allows the body to rid itself of flawed or extraneous cells.
The researchers knocked out the bax gene in mouse embryos, creating a gene defect that seemed to produce no harmful effects in the animals later in life. In fact, they live longer than normal mice.
Egg follicles continued to develop in the ovaries of the bax-less mice as late as 22 months, ancient by mouse longevity standards. However, the females did not become pregnant when caged with male mice, which Tilly thinks is due to shutdown of sex hormones from the pituitary gland in the animals' brains.
When the researchers removed the eggs from their geriatric mice, they found they were capable of being fertilized in the test tube and of growing into normal-appearing embryos.
This story ran on page A01 of the Boston Globe on 02/01/99. © Copyright 1999 Globe Newspaper Company.