Scientists at the University of California, Berkeley, have uncovered how chronic stress can activate a hormone that reduces fertility, even long after the stress has ended. The study, conducted in rats, suggests that blocking this hormone may restore normal reproductive behavior in females. Researchers hope that this discovery could help women struggling with stress-related infertility.
Chronic stress is thought to play a significant role in the rising rates of infertility today. Studies show that about 75% of healthy couples under 30 have difficulty conceiving within three months of trying, and 15% struggle to conceive after a year.
“What’s amazing is that one gene controls the complex reproductive system, and by blocking it, we can completely change the reproductive outcome,” said Daniela Kaufer, an associate professor of integrative biology.
The hormone responsible is called gonadotropin inhibitory hormone (GnIH). First discovered in quail 15 years ago, GnIH was later found in humans under a different name, RFamide-related peptide (RFRP), by Kaufer’s colleague George Bentley. Their research demonstrated that stress in male rats increased the production of RFRP, and a similar effect was observed in female rats. However, the elevated levels of RFRP lasted much longer in females than in males.
Collaborating with UC Berkeley colleagues Lance Kriegsfeld and several graduate and undergraduate students, Kaufer and Bentley led the new study. They found that GnIH levels in the brain’s hypothalamus remained elevated for an entire estrus cycle (similar to the human menstrual cycle) after the stress had ended. When researchers reduced GnIH levels, they were able to restore normal reproductive behaviors.
“GnIH appears to be the main factor, and by reducing its levels, we returned reproductive functions to normal,” Kaufer explained.
Bentley added that since human GnIH is present in the brain and ovaries, its manipulation could potentially help treat infertility in women. Their findings will be published in the January 13 issue of eLife.
Improving Breeding in Captive Animals
The discovery also holds promise for improving breeding success in captive animals, particularly those endangered species facing chronic low-level stress. Bentley believes that long-term stress can elevate glucocorticoid hormones, which might interfere with GnIH and prevent ovulation in female animals.
“We think we can block GnIH to improve reproduction in animals,” Bentley said. “The biology is there, and we can potentially manipulate it to help species breed successfully.”
Additionally, Kaufer and Bentley are working on a project funded by the Michelson Grant from the Found Animals Foundation. This research aims to use RFRP to induce permanent infertility in feral animals, such as cats and dogs, without the need for physical capture or neutering.
Stress and Reproductive Health
The link between stress and fertility is thought to be adaptive, helping to prevent births during times of scarcity. However, chronic stress can significantly impact both men and women’s fertility, especially women’s ability to conceive or carry a pregnancy to term.
In their experiments, the UC Berkeley researchers subjected female rats to chronic stress by confining them for three hours a day over 18 days, followed by a four-day relaxation period. While the stress hormone cortisol returned to normal during the relaxation period, the levels of RFRP3 remained high, and reproductive behavior did not recover as expected. Female rats that were stressed showed a 20% pregnancy rate, compared to 80% in normal rats, and experienced more frequent miscarriages.
In a breakthrough step, the researchers used a virus to deliver an RNA blocker to reduce RFRP3 levels by 75% during the stress period. This intervention restored normal mating behavior, pregnancy rates, and reduced embryo resorption, showing that blocking GnIH can counteract the negative effects of stress on fertility.
“This research shows that even if chronic stress isn’t severe enough to stop the menstrual cycle, it can still impair fertility,” said Kriegsfeld.
This study provides new insights into how stress affects reproductive health and opens the door for potential treatments for women experiencing stress-related infertility.
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