Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption

Infertility has become alarmingly common in otherwise healthy women and around 15% of healthy couples younger than 30 years old are unable to conceive within the first year of trying. High-stress levels are known to decrease short-term fertility in humans and other animals, which may serve to prevent pregnancy during times when food or other resources are in short supply. However, it is not clear if exposure to stress has lasting effects on fertility. Previous studies have found that when male rats experience stress, they release a protein called RFRP3. This protein inhibits brain activity, leading to a reduction in the release of reproductive hormones. Geraghty et al. took a closer look at how stress may cause lasting fertility problems in female rats. The researchers exposed female rats to stress by restricting their movements for 3 hr each day over the course of 18 days, which increased the levels of stress hormones in the animals. They allowed the rats to recover for one full reproductive cycle—equivalent to a month in humans—and found that while their stress hormone levels returned to normal, RFRP3 levels in the brain remained high. Even after the recovery period, the females were less likely to mate. Also, the females that did mate were less likely to become pregnant, and the ones that did were more likely to lose some of the embryos. Overall, the level of reproductive success in these rats was only 21%, down from 76% in the control group (who were not exposed to the stress). Next, Geraghty et al. injected a genetically engineered virus into the brain of the stressed rats to switch off the gene that makes RFRP3 during the stress period. This reduced the levels of the RFRP3 protein and restored the mating, pregnancy, and embryo survival rates to the normal levels seen in unstressed rats. These results suggest that increased levels of RFRP3 during stress can have lasting negative effects on fertility. In the future, developing therapies that lower RFRP3 levels may help individuals who experience fertility problems.