Feb. 11, 2005 Berkeley -- Shift workers and travelers who pop melatonin pills to stave off drowsiness or jetlag have another reason to be cautious about taking the supplement, say Japanese and University of California, Berkeley, researchers.
A new study shows that melatonin, a hormone available without prescription, has broader effects in the brain than once thought. In experiments on the Japanese quail, the researchers found that melatonin switches on a recently discovered hormone called gonadotropin inhibitory hormone (GnIH), which has been found to have the opposite effect to the key hormone priming the body for sex – gonadotropin releasing hormone (GnRH). In birds, switching off GnRH causes the gonads – testes and ovary – to shrink as part of the birds' yearly cycle.
Though the role of melatonin is likely to be more complex in humans, the fact that the hormone has such a big effect on birds suggests it could have significant though unnoticed effects in humans, said George E. Bentley, an assistant professor of integrative biology at UC Berkeley. In humans, GnRH – one of various short protein or peptide hormones referred to as neuropeptides – brings on puberty.
"This is quite exciting in terms of potential effects of melatonin on the reproductive axis, that is, the link between the brain, the pituitary gland and the gonads," said Bentley, who is finishing post-doctoral work at the University of Washington, Seattle, before a planned move this summer to UC Berkeley. "Melatonin has not been considered to have an effect on any neuropeptide in the brain of any vertebrate. If melatonin can do this on one neuropeptide system, it has the potential to do it on any other neuropeptide system."
Bentley noted that melatonin could have good as well as bad effects, but that the current lack of knowledge of the hormone's function in the human brain is troubling.
"It really amazes me that melatonin is available in any pharmacy," Bentley said. "It is a powerful hormone, and yet people don't realize that it's as 'powerful' as any steroid. I'm sure that many people who take it wouldn't take steroids so glibly. It could have a multitude of effects on the underlying physiology of an organism, but we know so little about how it interacts with other hormone systems."
Bentley, along with graduate student Takayoshi Ubuka, senior endocrinologist Kazuyoshi Tsutsui, a professor on the faculty of integrated arts and sciences, and their colleagues at Hiroshima University, report their findings this week in the Online Early Edition of the Proceedings of the National Academy of Sciences.
Melatonin regulates the sleep-wake cycle, or circadian rhythms, in many animals, including humans. Produced at night by the pineal gland at the base of the brain, it makes us drowsy at night and, when levels drop in the morning, brings us back to alertness. As an over-the-counter supplement, it is used widely to stave off jetlag from long airline flights, and is popped nightly by many nightshift workers to keep alert.
Despite claims by supplement manufacturers, however, melatonin has shown mixed results as a treatment for disease, whether insomnia, Alzheimer's disease or cancer. It is not recommended for children, for women trying to get pregnant or breast-feeding mothers.
Bentley got interested in melatonin's effects in the brain through his work with Tsutsui on a new brain hormone, GnIH, that Tsutsui discovered in 2000. GnIH's discovery got a lot of attention at the time because it was one of the last remaining pieces of the brain's hormone system that controls reproduction. While most hormones produced by the brain have both agonists, called "releasing hormones," to switch them on and antagonists to switch them off, GnRH was missing an antagonist. GnIH seemed to be that missing antagonist, and work by Tsutsui and Bentley confirmed its role in turning down production of GnRH and thus switching off the gonads. Though most of these studies were conducted on the Japanese quail or the white-crowned sparrow, a search of the human genome shows that humans have a gene for the same hormone.
"This is a way in which puberty could be regulated, for example," Bentley said. "It adds a whole new dimension to reproductive biology, because there are a lot of clinical issues with reproduction and puberty. One side of the picture was missing (until) this new hormone came into play."
"Reproduction is something that has been studied very rigorously, and to identify a new peptide in that arena that seems to be playing such an important role is pretty phenomenal at this time," added Lance Kriegsfeld, an assistant professor of psychology at UC Berkeley who is collaborating with Tsutsui and Bentley on similar research.
In an effort to find out what regulates GnIH, Bentley again teamed up with Tsutsui and his laboratory colleagues to look at the effects of melatonin. Though birds make melatonin in the same way humans do, and the melatonin cycles through the day and through the year with changes in the length of the day, it's unclear the role it plays in the brain.
Ubuka in Japan removed all the organs in the Japanese quail, Coturnix japonica, that are known to produce melatonin and found that GnIH levels dropped significantly. When melatonin levels were increased with injections, however, GnIH levels more than tripled. Afterward, the bird brains were sent to Bentley to test for the presence and location of melatonin binding sites.
"We found that melatonin actually increases production of the messenger RNA and the mature peptide, GnIH, and it appeared to be a direct effect. The melatonin is binding to the GnIH neurons in the hypothalamus of quail," he said.
To look more closely at the role melatonin plays in the reproductive cycle of quail, the researchers also raised male birds under different lighting conditions. Quail raised in simulated short days, which would be expected to produce high levels of melatonin in the brain, had correspondingly higher levels of GnIH than did quail raised with longer periods of light, which would be expected to produce less melatonin. In addition, the short-day males had larger testicles than the long-day males.
Further support for the importance of melatonin in the reproductive cycle of males came from biologist John Wingfield's University of Washington lab, where Bentley looked for sites where melatonin binds (and therefore has physiological effects) in the quail brain. He found it bound to the same areas that produce GnIH, which are located in the periventricular nucleus.
"There are a lot of unknowns in terms of potential effects of melatonin," Bentley said. "We know that GnIH affects the reproductive axis, but the GnIH neurons in the hypothalamus have fibers branching from them that transport the peptide around the brain to multiple brain areas – areas involved in basically every physiological and behavioral process you could imagine. So melatonin could affect a multitude of physiological systems via the GnIH system."
In birds, the melatonin is clearly mediating a seasonal reproductive process already known to occur, the researchers said. For mammals, however, the implications are still unclear, since human reproduction seems only slightly affected by seasonal changes.
"GnIH likely has implications for regulating the human reproductive axis, but the mechanisms by which melatonin may act on this population of cells to regulate the changes in seasonal reproduction that we see in humans remains to be determined," Kriegsfeld said.
Bentley and Kriegsfeld, in collaboration with Tsutsui, plan to look at melatonin's role in the brain and reproductive cycle of a photoperiodic mammal, the Siberian hamster, which they've shown contains GnIH.
In addition to Ubuka, who will follow Bentley to UC Berkeley this summer, the paper's other coauthors are Hiroshima University post-doctoral fellow Kazuyoshi Ukena, who was instrumental in the initial discovery of GnIH, and Wingfield, Bentley's University of Washington advisor and a professor of biology. Tsutsui, Ubuka and Ukena also are affiliated with the Core Research for Evolutional Science and Technology at Tokyo's Japan Science and Technology Corporation.
The work was funded in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology, and by the National Institutes of Health (USA).
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