BLOCKING HORMONE COULD ELIMINATE STRESS-INDUCED INFERTILITY

University of California, Berkeley, scientists have discovered that chronic stress activates a hormone that reduces fertility long after the stress has ended, and that blocking this hormone returns female reproductive behavior to normal.

While the experiments were conducted in rats, the researchers are optimistic that blocking the gene for the hormone – called gonadotropin inhibitory hormone (GnIH) – could help women overcome the negative reproductive consequences of stress.

Stress is thought to be a major contributor to today’s high levels of infertility: Approximately three-quarters of healthy couples under 30 have trouble conceiving within three months of first trying, while 15 percent are unable to conceive after a year.

“What’s absolutely amazing is that one single gene controls this complex reproductive system, and that you can elegantly knock this gene down and change the reproductive outcome completely,” said Daniela Kaufer, an associate professor of integrative biology.

GnIH was discovered only 15 years ago, in quail, and found to be a powerful suppressor of fertility. Its mammalian equivalent, RFRP (RFamide-related peptide), was isolated in humans in 2009 by Kaufer’s UC Berkeley colleague George Bentley, an associate professor of integrative biology.

Bentley and Kaufer later found that exposing male rats to stress increased the brain’s production of RFRP. The new study found similar negative effects on fertility in female rats, though the increased levels of RFRP caused by chronic stress last much longer in females than in males. Three UC Berkeley labs – those of Kaufer, Bentley and Lance Kriegsfeld, an associate professor of psychology – collaborated on the study, which was led by graduate student Anna Geraghty and undergraduate Sandra Muroy.

“GnIH seems to be the main player, because it is elevated in the brain’s hypothalamus for a full estrus cycle after the stress ends,” Kaufer said. “When we knocked down levels of GnIH, we restored all reproductive behavior back to normal.”

“We know that human GnIH is present in the human brain and gonads, and that it inhibits the production of steroids in human ovaries, so certainly the potential is there for it to be manipulated to address human infertility,” Bentley said.

Relieving stress to allow captive breeding

Bentley is also excited about the potential to knock down GnIH to improve breeding success in captive animals, in particular those threatened with extinction in the wild.

“A lot of wild birds and vertebrates won’t breed in captivity in part, we think, because of chronic low-level stress,” Bentley said. “Just a chronic slight elevation in glucocorticoid stress hormones might influence the GnIH system and inhibit reproduction sufficiently to stop females from ovulating properly.”

Blocking the GnIH gene via gene therapy might alleviate this chronic stressor, he said. “The biology is there; I think we can do it.”

He and Kaufer are also involved in attempts, funded by a Michelson grant from the Found Animals Foundation, to boost RFRP hormone in mammals to induce permanent infertility in feral animals without the need to capture and neuter them.

“If the role of GnIH plays out to be a fundamental mechanism for integrating stress into the reproductive axis, we think we can turn it around the other way and overexpress RFRP in the brain and gonads and cause infertility in pest species or feral cats and dogs,” he said.

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