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Genetic switch controls stress-induced infertility

by Kurt Kleiner
Jan 29 / 15

Chronic stress has long been known to reduce fertility. Now new research in rats shows that the effect can last long after the stress is over. The research has also uncovered the molecular mechanism that causes the infertility, and identified a potential target for treatment.

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A schematic shows the control group of rats on the left mated less, had fewer pregnancies, and smaller litter sizes when exposed to stress. Rats treated with a genetically engineered virus to block a specific peptide, right, had the same fertility whether they were stressed or unstressed. 
Image courtesy of E-Life


The new work by Daniela Kaufer (University of California, Berkeley), a fellow in CIFAR’s program in Child & Brain Development, and colleagues Anna Geraghty, Sandra Muroy, Lance Kriegsfeld and George Bentley, shows the important role of a neural peptide that controls a number of functions related to fertility.

The peptide, called RFRP3, acts as an inhibitory switch of the reproductive axis. It is expressed at high levels prior to puberty and falls when sexual development begins. The new work shows that chronic stress increases the levels of RFRP3 expression in the brain and inhibits sexual interest in rats, and decreases their likelihood of giving birth when they do engage in mating.

“Our study shows that the dramatic decrease of reproductive function lingers well beyond the end of stress, and beyond the time when we see high levels of stress hormones in the blood,” Kaufer says.

To conduct the study, the researchers induced stress in female rats by restricting their movements for three hours a day for 18 days, which increased the levels of stress hormones. After four days of recovery – a full reproductive cycle in rats — stress hormone levels had dropped, but RFRP3 levels were still high.

Even after the four-day recovery the rats subjected to the stress were less likely to mate, less likely to become pregnant if they did mate, and more likely to lose some embryos if they did become pregnant. Overall, their reproductive success was only 21 per cent compared with 76 per cent with unstressed rats.

As the final part of the experiment, the researchers injected a genetically engineered virus into the rats that shut off the gene that makes RFRP3 during the stress period. With the gene switched off the levels of mating, pregnancy, and embryo survival all returned to normal.

Kaufer says that RFRP3 seems to work as a “master switch” for controlling reproduction. It’s high in childhood, then decreases as puberty sets in. It may also play a role in the onset of menopause and in controlling the estrous cycle.

The peptide also seems to have evolved as a way of slowing down reproduction under stressful conditions. Stress is often a signal that conditions aren’t ideal for raising young because of conditions like food shortages or overpopulation. A switch that delays pregnancy until after the stress is gone could help ensure the survival of the offspring.

Kaufer says that the finding could point to a treatment for human infertility, which can also be influenced by stress. Although it’s unlikely a genetically engineered virus would be used on humans, the gene and the RFRP3 peptide could be useful targets for a drug.

“I think we’re pointing to the target that now we should look for pharmacological ways to modulate that,” Kaufer says.