by Robert Sanders
Credit: Dollar Photo Club
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.
The researchers will publish their findings in the Jan. 13 issue of the journal eLife.
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.
Stress and fertility
The effect of stress on reproduction is thought to be adaptive, preventing new births during times of scarcity or social disruption. Chronic stress can decrease the sex drive in both men and women, but also affect women's ability to get pregnant and carry a fetus to term. Even the stress of trying to conceive can lower women's chances. Tales abound of couples who adopt because they can't conceive and suddenly become new biological parents.
To test the effects of chronic stress on female rats, Geraghty confined female rats for three hours a day for 18 days, then let the rats relax for four days - the rat's typical estrus period, akin to women's 28-day menstrual period. By the end of that stress-free hiatus, cortisol levels had returned to normal, though levels of the inhibitory hormone, called RFRP3 in rats, were still elevated.
"Even after the chronic stress was gone and levels of the stress hormone cortisol had returned to normal, we still saw a decrease in reproductive behavior: from an 80 percent pregnancy rate in normal rats to 20 percent in those who should have recovered from stress," Kriegsfeld said. The 20 percent that actually got pregnant also experienced an increased incidence of embryo resorption of the fetus - the equivalent of a miscarriage.
Geraghty then used a virus developed in Kriegsfeld's laboratory to insert into the brain an RNA blocker of the RFRP3 gene, which knocked down levels of the peptide hormone by about 75 percent during the period of chronic stress. She turned the gene back on after the stress ended in case it also plays a role during pregnancy.
"The knock-down RNA delivered during the period of chronic stress restored all subsequent reproductive behavior to normal: Mating behavior, pregnancy rate and the amount of embryo resorption were all back to normal," Geraghty said.
"This study shows that even when chronic stress is not that extreme to where you stop your cycle, as when women under caloric restriction get amenorrhea, reproductive function is still hampered."
Explore further: Biology of love at first sight: Study explains the mechanism of "Cupid's arrow"
More information: Knockdown of hypothalamic RFRP3 prevents chronic stress induced infertility and embryo resorption, eLife, 2014.
Medical Xpress on facebook
Related Stories
Stress puts double whammy on reproductive system, fertility
Jun 16, 2009
University of California, Berkeley, researchers have found what they think is a critical and, until now, missing piece of the puzzle about how stress causes sexual dysfunction and infertility.
Biology of love at first sight: Study explains the mechanism of "Cupid's arrow"
Aug 15, 2014
Waseda university researchers have identified certain chemicals in the brain which regulate downstream reproductive hormones of males.
New human reproductive hormone could lead to novel contraceptives
Dec 22, 2009
(PhysOrg.com) -- Nearly 10 years after the discovery that birds make a hormone that suppresses reproduction, University of California, Berkeley, neuroscientists have established that humans make it too, opening ...
Discovery of mechanism by which sex hormone regulates aggressive behavior
Jan 29, 2014
A group led by Professor Kazuyoshi Tsutsui and Research Associate Takayoshi Ubuka, of the Waseda University Center for Advanced Biomedical Sciences, has discovered a hormonal mechanism for controlling aggressiveness in male ...
'Trigger' for stress processes discovered in the brain
Nov 27, 2014
At the Center for Brain Research at the MedUni Vienna an important factor for stress has been identified in collaboration with the Karolinska Institutet in Stockholm (Sweden). This is the protein secretagogin ...
Recommended for you
Scientists design nicotine vaccine that provokes robust immune response
11 hours ago
When a promising nicotine vaccine failed in clinical trials a few years ago, scientists from The Scripps Research Institute (TSRI) were determined to keep trying to help smokers overcome their addiction.
Researchers identify mechanism involved in causing cataracts in mice
11 hours ago
Cataract is one of the most common eye diseases, becoming more prevalent as people age. Over half of adults in the United States develop cataracts before age 80 and more than six million have undergone surgery ...
BPA and BPS affect embryonic brain development in zebrafish
11 hours ago
Bisphenol A, known as BPA, is produced in massive quantities around the world for use in consumer products, including household plastics. In response to public concerns, many manufacturers have replaced BPA ...
Sound mind, strong heart: Same protein sustains both
11 hours ago
A Roman philosopher was the first to note the relationship between a sound mind and a sound body. Now the findings of a new Johns Hopkins study reveal a possible biochemical explanation behind this ancient observation.
Researchers uncover more clues to how drug reverses obesity, diabetes, fatty liver disease
14 hours ago
Researchers at the University of Michigan have identified how a promising drug in clinical trials for the treatment of obesity and related metabolic disorders improves the metabolism of sugar by generating a new signal between ...
Is stem cell therapy less effective in older patients with chronic diseases?
14 hours ago
A promising new therapeutic approach to treat a variety of diseases involves taking a patient's own cells, turning them into stem cells, and then deriving targeted cell types such as muscle or nerve cells ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
by Robert Sanders
Credit: Dollar Photo Club
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.
The researchers will publish their findings in the Jan. 13 issue of the journal eLife.
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.
Stress and fertility
The effect of stress on reproduction is thought to be adaptive, preventing new births during times of scarcity or social disruption. Chronic stress can decrease the sex drive in both men and women, but also affect women's ability to get pregnant and carry a fetus to term. Even the stress of trying to conceive can lower women's chances. Tales abound of couples who adopt because they can't conceive and suddenly become new biological parents.
To test the effects of chronic stress on female rats, Geraghty confined female rats for three hours a day for 18 days, then let the rats relax for four days - the rat's typical estrus period, akin to women's 28-day menstrual period. By the end of that stress-free hiatus, cortisol levels had returned to normal, though levels of the inhibitory hormone, called RFRP3 in rats, were still elevated.
"Even after the chronic stress was gone and levels of the stress hormone cortisol had returned to normal, we still saw a decrease in reproductive behavior: from an 80 percent pregnancy rate in normal rats to 20 percent in those who should have recovered from stress," Kriegsfeld said. The 20 percent that actually got pregnant also experienced an increased incidence of embryo resorption of the fetus - the equivalent of a miscarriage.
Geraghty then used a virus developed in Kriegsfeld's laboratory to insert into the brain an RNA blocker of the RFRP3 gene, which knocked down levels of the peptide hormone by about 75 percent during the period of chronic stress. She turned the gene back on after the stress ended in case it also plays a role during pregnancy.
"The knock-down RNA delivered during the period of chronic stress restored all subsequent reproductive behavior to normal: Mating behavior, pregnancy rate and the amount of embryo resorption were all back to normal," Geraghty said.
"This study shows that even when chronic stress is not that extreme to where you stop your cycle, as when women under caloric restriction get amenorrhea, reproductive function is still hampered."
Explore further: Biology of love at first sight: Study explains the mechanism of "Cupid's arrow"
More information: Knockdown of hypothalamic RFRP3 prevents chronic stress induced infertility and embryo resorption, eLife, 2014.
Medical Xpress on facebook
Related Stories
Stress puts double whammy on reproductive system, fertility
Jun 16, 2009
University of California, Berkeley, researchers have found what they think is a critical and, until now, missing piece of the puzzle about how stress causes sexual dysfunction and infertility.
Biology of love at first sight: Study explains the mechanism of "Cupid's arrow"
Aug 15, 2014
Waseda university researchers have identified certain chemicals in the brain which regulate downstream reproductive hormones of males.
New human reproductive hormone could lead to novel contraceptives
Dec 22, 2009
(PhysOrg.com) -- Nearly 10 years after the discovery that birds make a hormone that suppresses reproduction, University of California, Berkeley, neuroscientists have established that humans make it too, opening ...
Discovery of mechanism by which sex hormone regulates aggressive behavior
Jan 29, 2014
A group led by Professor Kazuyoshi Tsutsui and Research Associate Takayoshi Ubuka, of the Waseda University Center for Advanced Biomedical Sciences, has discovered a hormonal mechanism for controlling aggressiveness in male ...
'Trigger' for stress processes discovered in the brain
Nov 27, 2014
At the Center for Brain Research at the MedUni Vienna an important factor for stress has been identified in collaboration with the Karolinska Institutet in Stockholm (Sweden). This is the protein secretagogin ...
Recommended for you
Scientists design nicotine vaccine that provokes robust immune response
11 hours ago
When a promising nicotine vaccine failed in clinical trials a few years ago, scientists from The Scripps Research Institute (TSRI) were determined to keep trying to help smokers overcome their addiction.
Researchers identify mechanism involved in causing cataracts in mice
11 hours ago
Cataract is one of the most common eye diseases, becoming more prevalent as people age. Over half of adults in the United States develop cataracts before age 80 and more than six million have undergone surgery ...
BPA and BPS affect embryonic brain development in zebrafish
11 hours ago
Bisphenol A, known as BPA, is produced in massive quantities around the world for use in consumer products, including household plastics. In response to public concerns, many manufacturers have replaced BPA ...
Sound mind, strong heart: Same protein sustains both
11 hours ago
A Roman philosopher was the first to note the relationship between a sound mind and a sound body. Now the findings of a new Johns Hopkins study reveal a possible biochemical explanation behind this ancient observation.
Researchers uncover more clues to how drug reverses obesity, diabetes, fatty liver disease
14 hours ago
Researchers at the University of Michigan have identified how a promising drug in clinical trials for the treatment of obesity and related metabolic disorders improves the metabolism of sugar by generating a new signal between ...
Is stem cell therapy less effective in older patients with chronic diseases?
14 hours ago
A promising new therapeutic approach to treat a variety of diseases involves taking a patient's own cells, turning them into stem cells, and then deriving targeted cell types such as muscle or nerve cells ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here
to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
0 comments:
Post a Comment