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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Jan 22, 2015

The release of the peptide RFamide-related (RFRP) increases under chronic
stress in both men and women — but for a longer amount of time in women.




Blocking GnIH could eliminate stress infertility

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

While the experiments were conducted in rats, 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 one year.

"What's absolutely amazing is that one single gene controls our complex reproductive system, and that you can elegantly lock this gene down and change the reproductive outcome completely," said Daniela Kaufer, an associate professor of integrative biology. Bentley and Kaufer had previously found exposing male rats to stress increased the production of RFRP (RFamide-related peptide) in their brain's. The new study found similar negative effects on fertility in female rats, though the increased levels of RFRP caused by chronic stress lasted much longer in females.

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

"GnIH seems to be the main player, because it is elevated in the brain's hypothalamus for a full estrus cycle even after 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 the potential is there for it to be manipulated to address human infertility," Bentley adds.

The research is published in the January 13 issue of eLife.

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."

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 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.

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, although levels of the inhibitory hormone, 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 - equivalent to a miscarriage.

Geraghty then used a virus developed in Kriegsfeld's laboratory to insert into the rat brain an RNA blocker for gene RFRP3. The RNA knocked down levels of the hormone by about 75 percent during 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."

Whereas it is well established that chronic stress induces female reproductive dysfunction, whether stress negatively impacts fertility and fecundity when applied prior to mating and pregnancy has not been explored. In this study, we show that stress that concludes 4 days prior to mating results in persistent and marked reproductive dysfunction, with fewer successful copulation events, fewer pregnancies in those that successfully mated, and increased embryo resorption. Chronic stress exposure led to elevated expression of the hypothalamic inhibitory peptide, RFamide-related peptide-3 (RFRP3), in regularly cycling females. Remarkably, genetic silencing of RFRP3 during stress using an inducible-targeted shRNA completely alleviates stress-induced infertility in female rats, resulting in mating and pregnancy success rates indistinguishable from non-stress controls. We show that chronic stress has long-term effects on pregnancy success, even post-stressor, that are mediated by RFRP3. This points to RFRP3 as a potential clinically relevant single target for stress-induced infertility.

DOI: http://dx.doi.org/10.7554/eLife.04316.001

Sheng Zhao, a psychology postdoctoral fellow, is also a co-author of the study. Kaufer, Bentley and Kriegsfeld are also members of UC Berkeley's Helen Wills Neuroscience Institute.

The work was supported by a BRAINS grant (R01 MH087495) from the National Institute of Mental Health and by the National Institute of Child Health and Human Development (R01 HD050470).

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