An image of Professor David Grattan showing the link between brain and fertility
Pictured: Professor Dave Grattan. Image courtesy of University of Otago.

About 25 per cent of New Zealand couples who are wanting to conceive may experience infertility or seek medical help. But thanks to a series of discoveries funded by the Health Research Council of New Zealand, new light is being shed on the mechanisms underlying infertility and the part played by key pathways within the brain.

In a University of Otago laboratory, Professor David Grattan may have just found a missing piece of the fertility puzzle. But his finding is best explained by going back a step, to a major discovery by Professor Allan Herbison that laid the groundwork for the latest revelation.

Professor Herbison, who heads the University of Otago-based Centre for Neuroendocrinology, had his latest findings published last November in the journal Proceedings of the National Academy of Sciences of the United States of America. In a landmark study, he’d identified a group of about 2000 kisspeptin neurons in the brain's hypothalamus which generate an hourly luteinizing hormone (LH) pulse that controls fertility in both females and males.

"We knew that episodic pulses control fertility, but the question for the past 40 years has been how does the brain do that? How does it manage to generate those pulses because the pulses are the key thing that determines fertility,” says Professor Herbison.

"If the LH hormone is at a continuous high level or a continuous low level, then reproduction shuts down – so it must be pulsatile. If it's not pulsatile or the pulses are at the wrong rate then it can cause infertility,” he explains. For example, when the pulses are too fast in women, it causes polycystic ovary syndrome (PCOS) and if they are too slow or non-existent, it leads to hypothalamic amenorrhea and infertility.

For Professor Herbison, the next step was to understand how this small group of kisspeptin neurons communicate to synchronise their hourly activity.

"Because we are working in the brain and it is incredibly complicated, we need to be developing new technologies that allow us to look at brain function better and in more detail.

"For example, we have developed a methodology where we can measure the activity of those key kisspeptin neurons online in real-time, all day and night, as an animal is moving about. Five years ago, that was only dreamed of."

Meanwhile, in a neighbouring lab, Professor Dave Grattan’s team has been busy finding another key piece of the fertility puzzle, focusing on the actions of the lactation hormone, prolactin, in the brain.

Elevated levels of prolactin have for many decades been known as a cause of infertility but – again – how it works has been a mystery. Building on the work of his colleague Allan Herbison, Professor Grattan is also now investigating the effect of prolactin on the pattern of LH pulses.

His latest research, funded by the Health Research Council, has found that administering just a single injection of prolactin appears to slow down and stop the LH pulses to the ovaries.

"We’re thinking that that's the mechanism where if you have chronically elevated prolactin, for example from a pituitary tumour, or physiologically such as in pregnancy or lactation, then the high prolactin is going to turn off the reproductive hormones.

"In lactation that's normal – it’s what you expect. But if you have high prolactin at the wrong time it causes infertility and that can happen whether you're a male or female.”

Professor Grattan’s key discovery has been to show the presence of prolactin receptors on the kisspeptin cells identified by Professor Herbison's research.

"The very recent data we've got, that I think is really exciting, is that when we knock out prolactin receptors in the kisspeptin cells we then lose the ability to suppress the LH pulses – they just carry on regardless. So it fits the idea that the way prolactin works is by directly suppressing the activity of the kisspeptin cells."

Both researchers are keen to bring together the discoveries made through the two projects and directly measure the effect of prolactin on kisspeptin activity and the pulses sent from that small group of neurons.

Expanding fundamental knowledge about the specific ways prolactin works has the potential to bring new treatments where couples struggle to conceive due to high prolactin levels.

"For the most part it can be treated effectively because it is so well known, but there might be more specific ways you can target a pathway rather than the sledgehammer type of approach of current treatments," says Professor Grattan.

For his colleague who has paved the way to more targeted research, involving new methodologies, Grattan has the greatest respect. "To be able to actually measure a population of neurons in a conscious animal and at the same time measure the hormonal output that is regulating – nobody else in the world has done that. It is absolutely cutting-edge stuff."

Other members of the Centre for Neuroendocrinology are partway through Health Research Council-funded projects involving fertility-related work. Professor Greg Anderson is examining metabolism and body weight to understand the impacts of obesity and undernutrition on fertility. And Associate Professor Rebecca Campbell is investigating the brain mechanisms leading to PCOS, which affects about 10 per cent of women. Findings from her research have just been published, showing that blocking androgen actions could help re-set reproductive function to normal levels by modifying brain circuitry important to fertility.

"The synergies of having multiple groups working on independent but related projects and having each of them developing different tools and ways of looking at it is incredibly valuable," says Professor Grattan.

Health Research Council chief executive Professor Kath McPherson says the discoveries taking place are the result of many years’ research and persistence by these researchers.

“It’s often the long-game with research like this – it takes time to find all the vital pieces in a complex process. David has successfully gained HRC support for prolactin research since 1997, and Allan since 2006. Bit by bit, their progress is advancing our knowledge of infertility causes, not just here but around the world.

“We’re really proud to be supporting work that increasingly looks as if it will, in time, help many people on their parenting journey.”

Pictured: Professor Dave Grattan. Image courtesy of the University of Otago.

A little extra: Kisspeptin was originally discovered by oncology researchers at the Pennsylvania State University College of Medicine, in Hershey, and was partly named after the hometown’s famous ‘Hershey’s Kiss’ chocolate. At the time, researchers had no idea that it had a role in fertility. Around 2003, kisspeptin was discovered to play a critical role in fertility.

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