Leptin Plays a Key Role in Women's Health

Newswise — A new study has found that leptin plays a critical role in women's reproductive and neuroendocrine health and suggests a future for the hormone in treating a number of conditions including exercise-induced bone loss, eating disorders and some cases of infertility. 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.

"We know that leptin is produced by the body's fat tissue and is secreted into the bloodstream in proportion to the amount of energy stored in fat," explains Mantzoros. "From there, it travels to the brain where it communicates exactly how much energy is available." In so doing, he adds, leptin regulates several key physiological functions that depend on adequate energy balance, including reproduction, metabolism, and bone formation.

Consequently, Mantzoros adds, 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," such that her reproductive and metabolic health are adversely affected. "Women stop menstruating and develop hypothalamic amenorrhea, their ovaries cease to function, and their levels of estrogen and other reproductive hormones drop dramatically," he says. Amenorrhea is also associated with abnormal levels of thyroid hormones and growth factors and loss of bone mass, which can lead to osteoporosis and bone fractures.

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

Eight of the 14 subjects received leptin twice a day, in doses that raised their blood leptin levels to those of normal women. Treatment continued until they responded, or up to three months. The remaining six subjects served as controls and received no treatment; they were observed for eight months. The subjects were observed both in a hospital setting and as outpatients.

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." The control group showed no change in their condition.

He adds that these findings are not only important for women dealing with disease states related to negative energy balance, but also have important implications for normal reproductive development, suggesting that 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. This is a landmark study that will improve many patients' lives in many ways."

Adds Mantzoros, "As a result of these findings, we're in the process of designing larger and longer studies to determine the safety, dose and efficacy of leptin treatment in these populations of women. This could eventually prove beneficial to patients with anorexia nervosa, competitive athletes with brittle bones, and last but not least, to approximately 30 percent of women whose infertility problems can be attributed to hypothalamic dysfunction."

In addition to Mantzoros and lead authors Jean Chan, MD of BIDMC and Corrine Welt, MD of MGH, co-authors include John Bullen, BA, and Aspasia Karalis, BS, of BIDMC; Patricia Smith, BS, of MGH; and Robyn Murphy, MS, and Alex DePaoli, MD, of Amgen, Inc.

This study was funded by grants from the National Institute of Health, Institute of Diabetes and Digestive and Kidney Diseases; the National Center for Research Resources; the Harvard Clinical Nutrition Research Center; the Harvard Center for Women's Health; and Amgen, Inc.

Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Care Center. For more information, visit www.bidmc.harvard.edu.