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Fat Hormone Revives Reproductive Systems of Lean Women
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Fat Hormone Revives Reproductive Systems of Lean Women
The researchers had been monitoring the weekly ultrasound results of the eight women in the pilot study with anticipation.
A study of amenorrheic women showed that leptin was necessary to revive and sustain reproductive function, reported Corrine Welt (right), Jean Chan, Christos Mantzoros, and colleagues. (Chan/Mantzoros photo by Phil Farnsworth; Welt photo by Steve Gilbert)
The women were fit and relatively lean--in great shape, except for their reproductive and other hormones, which were at low ebb, apparently from increased exercise or weight loss.
Twice a day, the women were injecting themselves with leptin, a hormone once thought to be a potential cure for obesity. Now, researchers wondered about its therapeutic powers on the lighter side of the scale. Could booster shots of the fat-derived hormone revive the women's dormant reproductive systems?
Barely one month into the experimental treatment, the ultrasound scan of one woman revealed that an egg had left the ovary. "The day we found out our first subject ovulated was the most exciting moment of the study," said endocrinologist Jean Chan, HMS instructor in medicine at Beth Israel Deaconess Medical Center. Another woman ovulated within a month, and a third ovulated after two months. When the study concluded at three months, two other women seemed on the verge of resuming monthly cycles, each with an enlarged pre-ovulatory follicle and withdrawal bleeding.
Later, the data analysis revealed that low doses of leptin rekindled the hormonal conversation between the brain and the ovaries, in stark contrast to the control group.
Leptin Link to Infertility
The findings show that low leptin levels may be responsible for reproductive and neuroendocrine abnormalities in the women, said endocrinologist Christos Mantzoros, HMS associate professor of medicine at BID and senior author of the paper, published in the Sept. 2 New England Journal of Medicine.
| "Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done." |
Generally, leptin circulates in direct proportion to the size of love handles: less fat means less leptin. But the hormone also responds quickly to a relative energy deficit. It fell to 20 percent of normal levels in men who fasted for several days, regardless of fat stores, the BID team found in an earlier study.
As a signal of energy deprivation, leptin seems to belong to an exquisitely sensitive system. For example, women in the study were not rabid exercisers or extraordinarily thin, Chan said, yet the women, ages 19 to 33, had stopped ovulating and menstruating for an average of five years. As a consequence of their low leptin levels, the women seemed to regress to a prepubertal hormonal state.
In the study, recombinant human leptin primed most of the women's reproductive systems within two weeks, Chan said. First came more frequent pulses of luteinizing hormone. The pituitary gland secretes luteinizing hormone in response to gonadotropin-releasing hormone from the nearby hypothalamus. In this case, the leptin may have stimulated the hypothalamus. In the treated women, estradiol levels surged. More subtle deficits in insulin-like growth factor-1 and thyroid hormone also improved. The women's ovaries enlarged, showing follicles with all the signs of maturing eggs. The signs and numbers dropped precipitously only one month after discontinuing leptin.
There were hints of improvements in bone density, as measured by increased markers of formation. The researchers are following up with a two-year study to investigate the effect of leptin on bone density and risk of fractures in up to 80 women.
The Pace of Leptin Research
This pilot study in women, supported in part by the National Institutes of Health, comes only nine years after leptin was first discovered in the grossly fat ob/ob mice, which lack the leptin gene, eat ravenously, and cannot reproduce. It marks an extraordinary pace of research from basic science to human trials, observed neuroendocrinologist Rexford Ahima of the University of Pennsylvania in an accompanying commentary."Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done," Ahima wrote. "This study represents a further step in unraveling the role of leptin in reproduction and neuroendocrine regulation."
When leptin was first discovered by Jeffrey Friedman of Rockefeller University, Mantzoros was a clinical research fellow in the BID lab of Jeffrey Flier, the George C. Reisman professor of medicine at HMS. They did not rush to follow the tantalizing promise of leptin for treating obesity. First, they wanted to understand leptin physiology in mice. Then, they moved onto observational studies in humans. Instead of playing a role in obesity, leptin probably works at the other end of the spectrum, they and other researchers realized.
Last year, Chan, Mantzoros, and colleagues reported that leptin controls reproductive and other neuroendocrine hormones in normal healthy men (see Focus, May 2, 2003). In an interventional study, eight healthy men quickly depleted their normal leptin levels by fasting for three days. Leptin had the most striking effect on reproductive hormones, correcting the fasting-induced drop in testosterone. The findings confirmed what animal and observational studies had suggested, which led them to test leptin's role in the amenorrheic women.
--Carol Cruzan Morton