How stress causes infertility

It's well known that stress can interfere with fertility. But what's less well understood is how. It turns out that there's a stress-sensitive signal in the brain's hypothalamus that can block the release of the hormones that normally coordinate reproduction. UC Berkeley scientist Anna Geraghty found that temporarily deactivating this signal can prevent the effects of stress on reproduction in rats. Co-author on the study Daniela Kaufer spoke to Chris Smith...

Daniela - The first thing that you see and that you would expect to see is that there's a rise in the level of circulating stress hormones, what would be cortisol in people. You also have a rise in a peptide called gonadotropin-inhibitory peptide or in mammals it's called RFRP3. It's a top-down switch, if you want, of the reproductive system - it sort of shuts down the system.

Chris - Where does this come from, this inhibitory hormone, and what sorts of cells is it targeting? What's seeing it and what effect is it having?

Daniela - The RFP3 hormone is produced in an area of the brain called the hypothalamus. It is known to inhibit cells that produce GnRH, the gonadotropin-releasing hormone. So, controlling from the top, the hypothalamus pituitary-gonadal axis.

Chris - And the fact that it comes on in response to stress, it's downstream of the effects of stress. How is that achieved then?

Daniela - Several years ago, we looked at the cells that produced GnH and we found that they have the right receptors for the stress hormone, for the cortical steroid - cortisol. So, that's called a glucocorticoid receptor and that's expressed in the cells that produce GnH. And in response to this elevated stress signal, they start producing GnH and that stays around.

Chris - And then when a person recovers from stress or an animal recovers from stress, you would expect their cortisol levels to drop right down? Do you see, eventually, the inhibitory peptide falling off, or does it stay elevated?

Daniela - The furthest that we looked was one full oestrous cycle after distress. At this point we see the stress hormone that's going down so don't see any more glucocorticoids that are elevated, but the GnH is still elevated. We haven't looked further out at the expression but we did look at functional relevance of that. And when we look at what happens functionally to the animals, they still have difficulty in mating. Less of them that mated get pregnant and more of the ones that got pregnant have problems carrying the pregnancy throughout, and we see embryo survival that is decreased.

Chris - So, Anna. How did you explore what the relationship was between RFRP and the fertility effects?

Anna - So what we used in our study in our study was actually an inducible knockdown virus, and what that means is that the virus itself turns off the RFRP gene in the hypothalamus. And so we're putting it directly into the brain to shut it down. But what the inducible aspect of it is, is that we could actually control when that virus is on and off. And so what we were able to do is control the virus to such a degree that it was only turned off during that stressful period. So, the same period we did earlier where we found the fertility problems. We repeated those 18 days but during this time we blocked RFRP from being released - actually look at the effects RFRP increases might be causing in these. However, because it's inducible, we can actually turn it back on once the stress is over and what we found was that by turning off RFRP just during those 18 days, you completely prevented all those reproductive problems we saw in the stressed animals. And they actually had the same levels of stress hormones between the two groups. So, not having RFRP didn't change how they experienced the stress, just the downstream effects of it.

Chris - What do you think the implications are for what you found?

Anna - Oh. I think the possibilities are really great for what we could do, although, a lot of research needs to be done. The ability to start thinking about maybe it's not just the stress hormone we should be looking at when humans or animals are having fertility issues. That maybe it's something downstream of stress that might be persistent, even though the stress levels are normal. So, in this case RFRP, might give us a much wider range of problems to look for in fertility so that we could actually better identify problems humans are having.