Book Review

Female Fertility and the Body Fat Connection

N Engl J Med 2003; 348:869-870February 27, 2003

Article

Female Fertility and the Body Fat Connection
(Women in Culture and Society.) By Rose E. Frisch. 194 pp., illustrated. Chicago, University of Chicago Press, 2002. $20. ISBN: 0-226-26545-5

The idea that excessive exercise or undernutrition can postpone puberty, reduce fertility, or prevent menstruation is now so embedded in the body of medical knowledge that it is hard to believe that Frisch's pioneering studies, beginning in the late 1960s, of the reproductive consequences of an altered mass of depot fat were largely ignored or treated with skepticism. Her hypothesis — that a critical mass of body fat is the crucial trigger of gonadotropin secretion, both in developing girls and in mature women during reproductive life — was initially based on detailed analysis of worldwide demographic data and was later supported by highly focused clinical investigation.

As Frisch tells the story, her life's work began in an unlikely way. Returning to science after having raised her family, she was collaborating with Roger Revelle, former director of the Harvard Center for Population Studies, on a study of future global food needs. From their data on weight gain in populations around the world, they noted that poor rural girls had their peak rate of growth at an older age than did well-nourished urban girls. Since it was known at the time that a period of rapid growth precedes the onset of menarche, they analyzed several large population studies in the United States in which the rate of growth and the age at menarche had been assessed and found that the average weight at menarche was 103 lb (47 kg), whether the girls matured early or late. They realized that body weight was a more accurate predictor of the age at the onset of menstruation than was chronologic age. From this insight, they derived their hypothesis of a “critical” body weight, which was published in 1970. Their work was in harmony with much that was known about laboratory and domestic animals at the time, but its significance was not fully recognized by clinicians.

From 1970 until 2000, when she published her most recent clinical article (on the reduced incidence of breast cancer in former college athletes), Frisch devoted herself to studying the mechanisms by which body weight influences reproductive function and its importance to health and disease. Her findings and their interpretation make up the bulk of the book. Although she had not been trained in either reproductive physiology or clinical medicine, Frisch sought out collaborations with nutritionists, endocrinologists, exercise physiologists, ballet dancers, and athletic coaches. She made all of Boston, with its wealth of universities, students, and hospitals, her laboratory. Some of her most important collaborators were D. Mark Hegsted, a nutritionist at the Harvard School of Public Health; Janet W. McArthur, an endocrinologist at the Massachusetts General Hospital; Tenley Albright, a champion figure skater; Douglas Wilmore, a surgical physiologist at the Brigham and Woman's Hospital; Isaac Schiff, now chair of obstetrics and gynecology at the Massachusetts General Hospital; various teams of competitive runners and swimmers at Harvard and Radcliffe; and professional ballet dancers.

The conclusions of this work are now widely accepted. In otherwise healthy young women, a critical mass of body fat is the essential trigger of cyclical pituitary–ovarian function. In teleologic terms, this is so because a successful pregnancy requires approximately 50,000 calories stored in the form of fat. A critical body-fat mass determines the onset of menses. Excessive leanness, as in persons with anorexia nervosa and some competitive athletes and professional dancers, delays the onset of puberty; after menarche has been established, excessive leanness can cause impaired ovulation, infertility, and amenorrhea. Estrogen deficiency induced by excessive exercise (and decreased fat mass) is associated with premature osteoporosis, even in runners in whom bone formation has been stimulated by exercise. On the positive side, women who have been extremely active athletically have a much reduced risk of breast cancer, presumably because they have been exposed to lower levels of estrogen over time.

To clinicians, these insights have been invaluable for the evaluation of patients with delayed puberty and amenorrhea, and they have important social and medical implications for dancers and athletes. Though less well documented, critical body-fat mass is probably also important in determining pituitary gonadal activity in men.

Although these clinical findings are convincing, critical scientists these days expect a molecular mechanism to ensure belief. Happily, Jeffrey Friedman and colleagues have filled the gap. By rigorous genetic analysis of a particular strain of obese mice (ob/ob mice), they showed in 1994 that the fat cells of normal mice secrete a specific protein hormone, leptin, which is lacking in ob/ob mice. In both mice and humans, leptin levels are elevated by obesity and lowered by starvation. Though leptin was initially recognized as an appetite-regulating hormone, Chehab and colleagues went on to show that it stimulates gonadotropin secretion by activating gonadotropin-releasing hormone neurons in the hypothalamus.

The topic and the book Female Fertility and the Body Fat Connection are wonderful examples of how clinical science has evolved over the past generation. Keen clinical observation, intuition, and enormous drive and enthusiasm were required to establish the fact that the mass of fat cells in the body is somehow a crucial regulator of gonadotropin secretion. Genetic analysis in a basic-science laboratory investigating a seemingly unrelated topic — the mechanism of obesity in ob/ob mice — has led to a convincing molecular mechanism. Frisch recounts these discoveries in a down-to-earth, conversational style that is both scientifically valid and accessible to a nontechnical audience.

Seymour Reichlin, M.D., Ph.D.
6480 South Upper Valley Rd., Vail, AZ 85641
reichlin@dakotacom.net