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Biological Chemistry

Sex Therapy Lead From Bird Brains

Reproductive hormone previously detected in birds, rats, and fish has now been found in humans

by Sophie L. Rovner
January 18, 2010 | A version of this story appeared in Volume 88, Issue 3

Credit: Courtesy of George Bentley
Credit: Courtesy of George Bentley

A hormone first found in bird brains could have ramifications for human sexuality, a new study reveals.

Analogs of the hormone, which suppresses reproduction and sexual behavior in birds and some other species, have now been detected in humans (PLoS One, DOI: 10.1371/journal.pone.0008400). The discovery could yield a new class of contraceptives as well as treatments for early puberty, low libido, and infertility.

Kazuyoshi Tsutsui, a biologist at Waseda University, in Tokyo, and coauthor of the PLoS One paper, discovered the first example of the peptide hormone in quail brains a decade ago (Biochem. Biophys. Res. Commun. 2000, 275, 661). Tsutsui and his coworkers named it gonadotropin-inhibitory hormone (GnIH).

Since Tsutsui’s initial discovery of GnIH in quail, homologs belonging to the RFamide-related peptide (RFRP) family have been found in other birds, as well as in fish, frogs, rodents, and monkeys. Now, University of California, Berkeley, biologists George E. Bentley and Takayoshi Ubuka, along with Tsutsui and other colleagues, have isolated from human brain tissue two compounds that they believe are GnIH homologs. They have dubbed the compounds RFRP-1 and RFRP-3.

Because the reproduction-suppressing properties of GnIH “seem to be quite highly evolutionarily conserved across vertebrates, GnIH most likely inhibits reproductive function in humans” as well, Bentley says. “It is possible that it inhibits sexual behavior, too, although we have no data on this in humans yet,” he adds.

“Identifying the inhibitory hormone in humans forces us to revise our understanding of the control mechanism of human reproduction,” Ubuka says. “We hope this will stimulate clinical studies on people with precocious puberty or in the area of contraception.” Because reproductive hormones promote the growth of some types of cancer cells, GnIH or its derivatives might also work as anticancer agents.

In its normal role, GnIH opposes gonadotropin-releasing hormone (GnRH), a key player in the reproductive system. GnRH is produced by neurons in the hypothalamus and travels through the bloodstream to the pituitary gland, prompting it to release gonadotropin hormones that prime the body for sex and procreation.

GnIH, which is also produced by hypothalamic neurons, blocks GnRH through multiple avenues. In their PLoS One paper, Bentley and colleagues report that the neurons that produce GnIH extend fibers, or projections, that contact the neurons that produce GnRH. They identified a receptor for the human GnIHs on the GnRH neurons. The researchers believe that binding of GnIH to that receptor suppresses secretion of GnRH.

In addition, GnIH inhibits secretion of gonadotropins by the pituitary gland, which also possesses the GnIH receptor, the researchers showed. Finally, GnIH is produced in the reproductive organs that are the targets of gonadotropins—ovaries in females and testes in males—and impedes their release of sex steroids.

Bentley and Tsutsui have studied the effect of GnIH on the response of female sparrows to male sparrows. A female normally signals her willingness to mate by raising her tail and head, fluttering her wings, and vocalizing. The researchers showed that administering GnIH to a female sparrow dampens her mating ardor considerably—but only for a short time.

Bentley thinks GnIH acts as an easily reversible check on the reproductive system. Such a light restraint could be particularly useful in seasonal breeders, which include many birds and mammals. “Within the time frame of the breeding season, it might be wise to have a system whereby you can pause reproduction if there’s a stressful stimulus or if environmental conditions are not conducive to breeding,” he says. “We think GnIH is acting as a pause button, so you don’t have to shut down the whole reproductive machinery,” he explains. “You can just temporarily put a halt to the proceedings.”

Stress is known to cause sexual dysfunction and infertility. Bentley and colleagues recently showed that GnIH neurons have a receptor for the hormones released when an animal is stressed and that stress stimulates GnIH expression (Proc. Natl. Acad. Sci. USA 2009, 106, 11324).

GnIH neural function in birds and mammals is also affected by the hormone mel­atonin, Tsutsui says (Endocrinology 2010, 151, 271). Melatonin is involved in the sleep/wake and reproductive cycles, and its synthesis and release are regulated by day length. Binding of melatonin to receptors on GnIH neurons increases the release of GnIH. “Melatonin manipulation may offer means of manipulating reproduction in humans and other mammalian species,” Tsutsui says.

Greg M. Anderson, a biologist at New Zealand’s University of Otago who studies GnIH and GnRH, recommends that the latest results be interpreted with caution. “The paper by Ubuka et al. is the first to characterize the RFRP-1 and -3 neurons and their projections to GnRH neurons in the human hypothalamus,” Anderson says. But he questions whether RFRPs produced in the brain can escape the blood-brain barrier and enter the bloodstream. He is also not convinced that all RFRPs can inhibit gonadotropin synthesis and secretion (Endocrinology 2009, 150, 1413).

“Whether RFRP-1 and -3 are in fact GnIHs will remain controversial until they are detected at physiologically meaningful concentrations in the mammalian portal blood system,” which carries blood and hormones from the base of the hypothalamus to the pituitary gland, Anderson says.

Bentley and Tsutsui plan to study the compounds’ activities and physiological concentrations further. Bentley will also explore whether modulating RFRP levels can help endangered animals breed more successfully in captivity.



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