December 17, 1998
Harvard
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Fat, Fertility, Exercise and Cancer Linked, Says Frisch

By William J. Cromie
Gazette Staff

Rose Frisch. Photo by Rose Lincoln.

Rose Frisch discovered that women need a certain amount of fat to become fertile and stay that way. Then she and her colleagues found that leaner, athletic women have a lower risk of breast and other cancers than their weightier, more sedentary counterparts. The latter conclusion came from the first study to link regular exercise with a reduced risk of breast cancer.

"Your brain knows you will not be successful at reproduction if you don't have enough fat," says the Harvard scientist. "But too much fat increases the amount of estrogen in the body and can thereby raise the risk of getting cancer."

What puzzled her for many years is how the brain knows that the body has too little or too much fat. The answer came recently with the discovery of leptin, a hormone that carries signals from fat cells to the brain.

"It's a fascinating molecule that ties together 25 years of research on food, fertility, exercise, hormones, and cancer risk," notes Frisch, who is an associate professor of population sciences emerita.

Grace Wyshak and Frisch, both researchers at the Harvard School of Public Health, are analyzing data on 5,400 women who graduated from eight colleges, including Harvard-Radcliffe, Vassar, and the universities of Wisconsin and Southern California. They are comparing the health and cancer rates of those who were athletes with those who were not.

Frisch and Wyshak first studied alums from these schools 15 years ago. They found that women between 20 and 80 years old who were college athletes had significantly fewer cancers of the breast, ovaries, uterus, and cervix than their less physically active classmates. They also enjoyed a lower risk of adult-onset diabetes. Since their study - the first of its kind - other researchers have confirmed their findings.

Leaner women derive their advantage from the fact that fat makes estrogen. That hormone, in turn, causes cells of the breast, ovaries, and uterus to grow and divide more often. The more frequently cells divide, the greater the chance of a mutation in their genes that might lead to cancer. Leaner women are also less likely to develop resistance to insulin, a condition that can lead to diabetes.

Lean does not always mean lightweight. Frisch found that a woman athlete's body has 30 to 40 percent less fat than a sedentary female, although they both may weigh the same. The lean athlete may even weigh more because fat contains only 5 to 10 percent water whereas muscles are 80 percent water.

Fertility Needs Fat

Although now well-known, such facts emerged only after years of research by Frisch and other scientists. She and her colleagues were the first to observe that athletic activity can delay menarche, the beginning of regular menstruation.

If females, athletes or not, don't have enough body fat, they will not produce the hormones necessary for ovulation, Frisch showed. The cut-off for females who have completed growth (16-18 years) is 22 percent of body weight. For example, a 5-foot-5-inch woman needs to weigh more than 108 pounds to maintain her monthly cycles.

Frisch also found how sharp that cut-off can be while doing experiments with 181 female runners and swimmers at Harvard. One swimmer "turned off" her menstrual cycle by reducing her weight to only five pounds below the critical point. "I wanted to test your theory," she told Frisch. When she regained five pounds, her cycles started again.

"The phenomenon is completely reversible, even after four years without cycles," Frisch remarks.

"Women should not attempt to become pregnant when they lack the required body fat to produce the hormones required for ovulation," she continues. "Taking the hormones by injection can lead to miscarriages or low-weight babies. A simpler solution is to cut back on jogging and switch from no-fat to low-fat milk.'

Signaling the Brain

Frisch did part of her work on animals because "you can't cut up adolescents to measure how much fat versus muscle they contain. I learned one key point about fat and reproduction at an industry conference where meat producers addressed the issue that people want lean pork, but lean pigs don't reproduce well."

Pigs and humans experience a large increase in fat just before sexual maturation. To learn more about body changes in humans at this time, Frisch tracked 181 well-nourished, middle-class girls from birth to age 18, measuring changes in height, weight, and fat during their growth spurt, at menarche, and at completion of growth.

She found that girls gain about 120 percent fat, but only 44 percent in lean muscle mass, during adolescence. Boys, on the other hand, experience a large increase in muscle and a small gain in fat.

"When girls finish growing, their bodies are 26 to 28 percent fat, compared to about 12 percent for boys," Frisch notes. A normal 5-foot-5-inch female weighing 125 pounds would carry as much as 35 pounds of fat. That's equivalent to 144,000 calories. In situations where a regular supply of food is not guaranteed, a woman needs to store that much body fat to cover the cost of pregnancy and nursing.

At menarche, which in this country occurs at an average age of 12.5 to 12.8 years, girls' bodies contain about 22 percent fat. Improvements in nutrition, health, and living conditions have lowered menarche age from 17 years in 1800, to 14 years in 1900, to the present age, which has remained so since 1950.

"It won't get any earlier," Frisch states, "because menarche is tied to the rate of growth, and even well-nourished kids can't grow any faster. Conversely, factors that slow growth will delay menarche. These include undernutrition, chronic disease, athletic activity, and even high altitude. Girls who were ballet dancers or athletes before menarche raised their average age of menarche to 15.5 years."

Weight, fat, and puberty are obviously tied together, but how does the brain know when to begin releasing the hormones needed for reproduction? The answer eluded Frisch until 1995 when Jeffrey Friedman of Rockefeller University in New York discovered a gene that causes mice to grow massively obese. The gene controls leptin, a hormone that regulates appetite. When the gene is faulty, or mutated, it fails to discourage overeating in both mice and humans.

Under normal conditions, when fat cells become filled, they produce leptin, which travels to the brain and triggers a feeling of satiety. That activity takes place in the hypothalamus, a cherry-sized area of the brain behind the eyes that controls many functions, including appetite and reproduction.

"Since 1995, more than 600 scientific reports about leptin have been published," Frisch notes. Most of them have to do with how to manipulate the hormone's activity to control weight gain. But a growing number of researchers are following its role in reproduction. In one report, mutations in the leptin gene caused severe obesity and failure to achieve puberty in two young girls and one boy.

Recently, leptin has also been implicated in stimulating the growth of blood vessels that are necessary both for development of a fetus and for the survival of cancer tumors. "We still have a lot to learn about this molecule, Frisch says, "and about its role in food, fertility, and malignancy."

 


Copyright 1998 President and Fellows of Harvard College