Menopause Mouse
Authors: Beckman Mary 
Published: August 2003

Like a box of bonbons, a woman's ovaries gradually lose their contents. They start with a set number of eggs, which dwindles as she ages. Menopause arrives when the ovary releases its last egg, but most women start to experience symptoms such as hot flashes and mood swings 5 to 10 years earlier. Now, scientists studying fertility cycles have created mice that might help them find out what triggers this so-called perimenopause. These animals simulate an important aspect of human perimenopause: The number of egg-producing structures declines rapidly, and this loss eventually leads to a menopauselike condition. The work suggests that elimination of an ovarian protein might spur the onslaught of perimenopause and the end of a woman's reproductive years.

Women are born with all the eggs they'll ever have, housed in individual ovarian structures called follicles. Each month, follicle-stimulating hormone (FSH) prods a batch of follicles to nurture the eggs within. One follicle dominates and spews enough estrogen to quell the remaining ones, which die along with their eggs. When women are about 40 years old, their ovaries start running through follicles faster. This stage, perimenopause, is heralded by a rise in the concentration of FSH. At menopause, no follicles remain, and women begin to suffer a host of health problems such as thinning bones, weight gain, and heart disease (see
"More Than a Hot Flash"
).

Although mice don't have menstrual cycles, they do generate mature eggs every week upon stimulation by FSH. Danilovich and colleagues wanted to know what would happen if the mice ovaries couldn't respond to the hormone--a situation resembling that created by a follicle deficiency. In previous research, they had engineered mice lacking the gene that encodes a cell membrane receptor activated by FSH. Animals with no copies of this gene are sterile and suffer from health problems such as malformed uteri.
So the researchers turned their attention to mice that retain one gene copy--so-called heterozygotes--which are born healthy and reproduce but lose their fertility over time. In the new work, they found that 12-month-olds weighed 25% more than normal, and these middle-aged mice had 1/15 as many ovarian follicles. Although normal mice continue to produce pups into old age, heterozygote fertility decreased markedly and ended at middle age, paralleling the difficulty that older, perimenopausal women face when they try to get pregnant. Furthermore, hormone production in the receptor-deficient mice mirrored that in perimenopausal women: Estrogen and progesterone concentrations dove, testosterone concentrations climbed, and extra FSH coursed through the animals' bloodstreams. According to reproductive biologist and co-author M. Ram Sairam of McGill University in Montreal, Canada, what happens in the mice might simulate what happens to women as they lose follicles.
Neuroendocrinologist John Lu of the University of California, Los Angeles, says that the results suggest that waning numbers of FSH receptors accelerate ovarian aging and incite perimenopause. If the findings translate to humans, they could help researchers figure out how to delay perimenopause and thus menopause. Such an achievement might prevent the associated infirmities and slam the lid on egg loss.
--Mary Beckman; suggested by Lynnette Gerhold

N. Danilovich and M. R. Sairam, Haploinsufficiency of the follicle-stimulating hormone receptor accelerates oocyte loss inducing early reproductive senescence and biological aging in mice.
Biol. Reprod.
67
, 361-369 (2002).
[Abstract]
[Full Text]

N. Danilovich, D. Javeshghani, W. Xing, M. R. Sairam, Endocrine alterations and signaling changes associated with declining ovarian function and advanced biological aging in follicle-stimulating hormone receptor haploinsufficient mice.
Biol. Reprod.
67
, 370-378 (2002).
[Abstract]
[Full Text]