Appetite Hormone Restores Fertility

In an experiment conducted by researchers from Harvard Medical School, three women who had not had a period for as long as 14 years began menstruating. All were happy with the result.

The hormone, called leptin, has been trumpeted as an appetite suppressor and a possible treatment for obesity. This new research shows that “a clear connection also exists between fat, or energy storage, and the ability to reproduce,” says Corrine Welt, an assistant professor of medicine who works at Massachusetts General Hospital, a Harvard affiliate.

Taking the results a giant step further, the leader of the research team suggests that leptin may be necessary to turn on puberty in adolescent girls. “It appears that normal, healthy girls gain weight immediately prior to puberty,” notes Christos Mantzoros, a Harvard associate professor who works at the affiliated Beth Israel Deaconess Medical Center in Boston. “This suggests that leptin levels, which rise in response to an increase in body fat, are letting the body know that there’s enough energy available to sustain a pregnancy.”

The women whose fertility was boosted by leptin injections had stopped menstruating as a result of losing an abnormal amount of fat, mainly by overexercising. In their 20s and early 30s, they pared themselves down to carrying about 40 percent less fat than is average for women their age.

Such loss of menses, or amenorrhea, is also associated with abnormal levels of thyroid hormones and a loss of bone mass, which can lead to brittle, easily fractured bones. The findings thus raise the possibilities of new treatments for exercise-induced bone loss and for eating disorders, as well as for certain cases of infertility.

Previous experiments by the Mantzoros group also show that low testosterone levels in men can be raised by leptin under certain conditions.

Too thin to conceiveLeptin was discovered in 1994 by Jeffery Friedman, a scientist at Rockefeller University in New York City. For a time, it looked like the solution to the obesity epidemic in the United States. But that didn’t work out.

“Normally, if you eat too much, leptin will give you a full feeling that makes you stop,” Welt explains. “But there seems to be a threshold, a leptin level, that, once crossed, doesn’t help control your weight anymore.”

Mantzoros, Welt, and their colleagues, however, became intrigued with the reproductive effects of leptin on mice. Laboratory experiments revealed that female mice deficient in the hormone never reach puberty. But give them leptin and they quickly get pregnant.

Some women with rare mutations that turn off leptin receptors in the brain also fail to reach puberty. And decades ago, Rose Frisch of the Harvard School of Public Health showed that it’s possible for women to be too thin to conceive.

The Mantzoros team decided to put it all together by giving leptin injections to eight women who had not menstruated for years. “All of them were heavy exercisers who had no children and very little body fat,” Welt explains. Twice a day, they received leptin injections that raised the levels of that hormone to those of normal women.

The results were dramatic, according to Mantzoros and Welt. “Six of the eight women experienced bleeding. Three had full restoration of their menstrual cycles,” Welt notes. All started growing follicles, the sacs that contain eggs. In addition, tests indicate that their bones started to grow rather than losing mass. Their levels of thyroid and growth hormones rose. Even vaginal dryness was mitigated.

All of them were pleased with the result. “Those who began menstruating again felt very happy to have their first cycle in five or more years, despite the irritability, aches, and other physical and emotional symptoms of premenstrual syndrome,” Welt says. “One subject who had not menstruated for 14 years was thrilled to feel like a normal woman again.”

The effects are not lasting, however. When the leptin injections stop, so do the periods.

Help on the way?The research results are important for three groups of women. The largest, notes Mantzoros, “is made up of extremely thin women who are infertile. The second group consists of competitive athletes and dancers whose thin frames put them at a risk for developing osteoporosis and suffering bone fractures. The smallest, but most extreme group is composed of women who are battling eating disorders, such as anorexia nervosa.”

In the largest group, leptin does not signal the brain to begin the sequence of hormonal secretions needed for menstruation. “These women account for more than 30 percent of cases of amenorrhea in women of reproductive age,” Welt notes.

Infertility can be treated by injections of hormones that boost follicle and egg growth. However, such treatment results in a high rate of multiple births. “With leptin, the hope is to restart a normal menstrual cycle, yielding ovulation of one egg at a time,” Welt says.

Added to infertility, these women have a high risk of bone loss. Even if they gain the weight needed for pregnancy, that will not restore lost bone. Neither will taking estrogen, and this option has undesirable side effects that include increased risk of breast cancer.

Leptin may help women with anorexia and other eating disorders by correcting their energy balance. Before that happens, however, further research is needed to establish optimal dosages. “Women in our study lost some weight, and that’s something we don’t want to see in anorexics,” Welt points out.

For leptin to live up to these promises, more tests with more women need to be done. “We would want to compare a large number of women who take the hormone with a matched group who do not take it,” Welt explains. “We would also want to establish the correct dose and frequency of injection needed to improve leptin levels without causing weight loss.”

Amgen Inc., a California biotech company whose representatives participated in the Harvard study, is going ahead with such tests. Finally, researchers would like to reduce injections from twice a day to once a month, or to replace the needles with an infertility pill.