Medical Research: What is the background for this study? What are the main findings?
Response: RFRP3 in mammals has been well characterized as a negative regulator of the hormonal reproductive axis. It shuts down release of gonadotropins necessary for successful reproduction, similar to how stress inhibits reproduction. Our lab has previously shown that stress can directly regulate RFRP3 levels in males-both acute and chronic stress lead to an upregulation of RFRP3 levels in the male rat. As a followup to that study, we were interested in looking at whether this response was similar in females, and how that may affect long term fertility. We found that chronic (18 days) of stress led to an increase in RFRP3 levels all all stages of the estrous cycle. This increase was also sustained for at least 4 days, or one whole estrous cycle, after the stress ended- the equivalent to a month menstrual cycle in humans. In rats that were stressed and then allowed to recover for 4 days, animals that were stressed were significantly less successful at reproducing- 76% success rate in controls compared to 21% in the stressed animals. This was a result of a combination of deficits in the mating process- less stressed animals successfully copulated, those that did successfully mate had fewer pregnancies, and gave birth to smaller litters. However, utilizing an inducible virus to knockdown RFRP levels in the hypothalamus specifically during the stress period prevented all of these problems- stressed animals without stress-induced RFRP3 increases looked indistinguishable to controls.
Medical Research: What should clinicians and patients take away from your report?
Response: There is still a lot of work to be done before we can move this research to clinical study, however the possibility is definitely there for this to have clinical relevance. While RFRP3 has been isolated in humans, the mechanism of action in the brain has not yet been identified and much more research needs to be done. What we are hoping by publishing this work, though, is that more researchers begin investigating human RFRP3 as a potential clinical therapy for stress-induced infertility, and this opens up the field rapidly to increase understanding of RFRP in humans.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: Exploring each individual step of the reproductive process more carefully is absolutely the next step. We know that RFRP decreases mating success, pregnancy success and litter resorption, but we do not understand the precise mechanisms behind it, and whether it is different at each stage. Identifying the neural networks being negatively influenced by RFRP in reproduction will get us a much better idea of what´s going on. This will also help us to better elucidate similar networks in other species, so that this research can be utilized in fertility research across a wide range of species, not just humans. In captive breeding programs, where many species struggle to breed in high-stress environments, utilizing this study as a backbone for future work could help identify some of the problems these species are facing and increase the success of these programs.