Knocking down a single gene can help stop stress from causing infertility, miscarriage

Scientists from the University of California Berkeley have discovered that by knocking down a single gene, they can stop stress from causing female infertility and miscarriage - in rats.

Although stress has been linked to decreased sex drive, delayed pregnancy and an increase in miscarriages, this is the first time the molecular basis for the links has been explored.

The research, published in the open access journal eLife, was carried out in rats. The gene encodes for a hormone that is common across all mammals and the findings could apply to humans and to endangered animals whose survival depends on captive breeding.

"Remarkably, genetic silencing of a single chemical compound, a peptide called RFRP3, restores mating and pregnancy success to a rate indistinguishable from non-stress controls," says Professor Daniela Kaufer.

The team, from the Kaufer, Kriegsfeld and Bentley labs at Berkeley, also carried out the first investigation into the long-term impact of pre-conception stress on female reproductive fitness and pregnancy. They found marked and persistent reproductive dysfunction even after recovery from stress.

Stressed females were less motivated to mate, became pregnant less often and - in those that did copulate successfully - fewer live pups made it to term and were instead reabsorbed into the uterus. The findings show that the impact of stress lingers long after the stress has been removed. These marked effects were completely eliminated by knocking down RFRP3.

"A strikingly high proportion of healthy women struggle with fertility and our findings provide a new focus for the clinical study of human reproductive health," says the graduate student lead author Anna Geraghty.

RFRP3 is the mammalian equivalent of a hormone first identified in Japanese quail and is made in the hypothalamus portion of the brain. One way it exerts its effect on females is by decreasing the normal surge in hormones that accompanies ovulation. It may be directly regulated by the stress hormone corticosterone. However, even after recovery from stress, when corticosterone levels have returned to normal, RFRP3 was found to continue exerting its effect on reproduction.

Total reproductive success was determined by the percentage of females that successfully brought a litter to full term. This dropped from 80% in females not exposed to stress, to 20% in those previously exposed to stress. However, in those exposed to stress but with RFRP3 knocked down reproductive success was restored to 80%, and embryo survival was back up to 94%. In the future, developing therapies that lower RFRP3 levels may help individuals who experience stress-related infertility.

Source: eLife