Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Massachusetts General Hospital (MGH), the findings are described in the September 2 issue of The New England Journal of Medicine.

“There are three populations of women for whom this study has particular relevance,” explains senior author Christos Mantzoros, MD, Director of the Human Nutrition Research Unit and Clinical Research Overseer of the Department of Endocrinology at BIDMC and Associate Professor of Medicine at Harvard Medical School.

“The largest group,” he explains, “is made up of extremely thin women who are dealing with problems of infertility; the second group consists of competitive athletes and dancers whose thin frames put them at risk for developing osteoporosis and suffering bone fractures; and the smallest -- but most extreme -- group is women who are battling eating disorders, such as anorexia nervosa.” The common thread among all of these women, he adds, is that their conditions are characterized by extremely low levels of body fat.

First discovered in 1994, leptin is probably best recognized as an appetite and weight regulation hormone. But leptin also functions to signal the brain and other organs about dangerous states of very low energy availability.

In situations in which body fat is severely diminished -- after extreme dieting or exercise or in the case of an eating disorder, for example -- a woman’s body enters a state of “negative energy balance,” explains Mantzoros, such that her reproductive and metabolic health are adversely affected. “Women stop menstruating and develop hypothalamic amenorrhea,” he says.

To test whether administering leptin would restore positive energy balance, the researchers recruited 14 competitive female athletes, whose body fat typically measures about 40 percent less than the average woman. All of the subjects had been diagnosed with hypothalamic amenorrhea and had stopped menstruating an average of five and one-half years prior to the start of the study.

Within three months the leptin therapy demonstrated dramatic results, according to Mantzoros. “Levels of reproductive hormones were raised, and women’s menstrual periods and normal ovarian functioning were restored. In addition, when serum markers [reflecting bone density] were measured, we found significant improvement among the treated women.” A control group showed no change in their condition.

Leptin may be the impetus necessary for the onset of puberty in adolescent girls. “It appears that normal, healthy girls gain weight immediately prior to puberty,” says Mantzoros. “This suggests that leptin levels -- which rise in response to the increase in body fat -- are letting the body know that there is enough energy available to sustain a pregnancy.” Conversely, when women have conditions that leave them with very low energy availability, their bodies revert to a state similar to that of pre-pubertal conditions.

“This research is important in understanding both normal human physiology as well as the mechanisms leading to several different disease states,” notes Jeffrey M. Friedman, MD, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University who first discovered the leptin molecule in 1994.

“This study proves the concept that low leptin levels are responsible for the neuroendocrine abnormalities observed in energy-deficient states, such as anorexia nervosa, strenuously exercising female athletes and extremely thin women with hypothalamic amenorrhea," Friedman says. "This is a landmark study that will improve many patients’ lives in many ways.”