A key to understanding the brain’s role in triggering fertility has been identified through HRC-funded research at the University of Otago, Dunedin’s Centre for Neuroendocrinology, and published in the prominent international journal Nature Communications.
Led by neuroscientist Professor Allan Herbison, the research has provided clear proof of the critical part played by kisspeptin, a small signalling protein that acts on the gonadotropinreleasing hormone (GnRH) neurons in the brain. The landmark discovery opens the door to new fertility treatments and new forms of contraception.
Although it was already known that kisspeptin is important in fertility, researchers’ understanding of how and where it worked was still unclear.
Professor Herbison says kisspeptin signalling was thought to occur in the brain as well as in the pituitary gland, the ovaries, the testes, and the placenta.
“What we didn’t know was what the relative importance was. Is the kisspeptin signalling in the ovaries really the important thing, or is it the kisspeptin in the brain that’s critical?”
They set up a range of experiments using strains of genetically manipulated mice in which the kisspeptin receptor Gpr54 had been removed from the small population of about 1000 GnRH neurons in the brain. As a result those mice do not go through puberty and were left completely infertile.
“That tells us that the kisspeptin signalling for GnRH cells is absolutely critical for fertility. But the clincher experiment is where you take a mouse where kisspeptin signalling has been taken out of every zone on the body, and put the correct functioning kisspeptin receptor back into just the GnRH neurons.
“Now the only place where kisspeptin can act is on the GnRH neurons. Amazingly, those mice go through puberty and become fertile,” he says.
Professor Herbison says this one small population of cells in the brain tell the pituitary what to do, and the pituitary tells the ovaries or the testes what to do.
“It’s quite a black and white result. We can now say that kisspeptin signalling at the GnRH neuron is the key for fertility.”
He says kisspeptin has been evolutionarily conserved for reproduction for billions of years.
“You can go right back to invertebrates and find kisspeptin is a key molecule that is required for fertility. When you come across something that evolution hasn’t changed much you know you are onto something that is pretty important.”
Professor Herbison says the focus is now switching to how to use kisspeptin more effectively in fertility treatment, even though only a small percentage of people are infertile because of issues with kisspeptin signalling in the brain.
“These studies have shown us that kisspeptin signalling is very important and can override other causes of infertility because it is such a powerful activator of the whole system.”
They are already planning work with clinical partners on making kisspeptin part of IVF treatment cycles.
Professor Herbison says there is also scope to develop a kisspeptin antagonist. This could have a role in developing new forms of contraception and may also have relevance to diseases such as prostate cancer in which testosterone is a key driver.