Leptin blocks bone loss, raises thyroid levels in women with exercise amenorrhea
Kofi
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Source:
Harvard University
Date:
2004-09-24
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Appetite Hormone Restores Fertility
A hormone that regulates appetite has been used to restore fertility in
a small number of women.
At Massachusetts General Hospital in Boston, Corrine Welt (right) and
Judith Adams study pelvic images of women who had stopped menstruating
because of heavy exercising. Researcher Patricia Smith (background)
assumes the role of a patient. (Photo Credit: Jon Chase/Harvard News
Office)
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
there¹s 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 conceive Leptin 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 didn¹t 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, doesn¹t 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 it¹s 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 that¹s something we don¹t 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.
Editor's Note: The original news release can be found here.
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This story has been adapted from a news release issued by Harvard
University.