Making sense of the menopause

Cows, these days, get something of an environmentally bad rap, and that’s partly thanks to the methane they produce during digestion that contributes to greenhouse gas emissions. But scientists and farmers also have a problem with something else they generate a lot of: nitrogen-rich urine. And the issue is that they dispense too much of it in one go in one place. But now there might be an answer: toilet-training for cows! Eva Higginbotham spoke to lead author Lindsay Matthews from the University of Auckland...

Lindsay - Cows produce a lot of urine, you know, 20, 30 liters a day each

Eva - Uh, 20 to 30 litres a day of urine is an absolutely amazing amount! Do they just drink tons of water?

Lindsay - Well, they do, yes. You know, they're producing a lot of milk, they're eating a lot of food and they need to drink a lot of water. So they're drinking over a hundred litres of water each a day. It has to go somewhere! And it comes out in great gushes that the soil and the plants can't handle, so the nitrate in the urine gets converted into two polluting products in outdoor settings -  so you get the nitrate going through to the water, and you get the nitrate in the soil getting converted to nitrous oxide which is a really potent greenhouse gas. If you're in an indoor situation, you get the urine mixing with faeces and converting immediately to ammonia, which is also a problem for the animals and the environment.

Eva - And so you were trying to find a solution to what to do with all of this urine?

Lindsay - Yeah. So it occurred to us that if we could collect it at source, we could deal with it in an environmentally-friendly way. The nutrients could be reused, they're very good nutrients, it's just not in the quantity that they come out at in a small area. So the idea is to collect the urine, how do we do that? Well, the most obvious solution is to use a toilet. The only problem is that people in the past have tried to toilet train cattle, and haven't really had that much success. So this is what we were faced with as our solution.

Eva - What did you do?

Lindsay - We modelled the training a little bit on what you might do with a toddler, and one of the successful ways of toilet training toddlers is to put them on the toilet. So we had our metaphorical toilet, which was really just a wee room, and it obviously had to be clearly different from anything else otherwise it would be just another part of the barn. So it was green walls, green floor - AstroTurf floor, so not a concrete floor, it had a nice spongy floor. The other thing that was different about it is that if they urinated in there, they immediately got a reward. This was really the first exciting part of the training, is that they made that connection between the urination and the reward so quickly. You know, some of them within two or three urinations they were spinning around and waiting at the hopper for their little tasty treat of liquid molasses. Others took maybe five to ten urinations, but regardless, most of the animals learned this phase very quickly. The other challenge in taking it to application will be the training, and we think that needs to be automated because even though it's relatively quick, you need to be there to observe the animal if you're doing it manually. So we would have a system for automatically detecting urinations and linking that to an automatic delivery of reward. We see that as less of a challenging part of the process

Eva - It's like a robotic toilet trainer for cows

Lindsay - Exactly. Exactly.

Eva - And now that you've trained cows to use a toilet, do you think you could train them to do anything?

Lindsay - Well, within their physical capabilities? Yes. They've got way more ability than a lot of people think they have. And the speed of learning of this rather complex task in interrogating their own feelings, and bladder filling, and then responding appropriately, voluntarily controlling reflexes...that's massive. And so, yeah, we've got a lot of potential

Obesity is a very big problem in the UK – a 2020 survey in England found that almost 1 in 3 adults are obese, with around 2 thirds overweight. And according to the latest NHS statistics, there were over 1 million hospital admissions where obesity was a key factor in just one year of recording. But how do we go about tackling this? Taxing unhealthy foods and beverages is being tried and banning certain items altogether is also being talked about, but in a free society these sorts of restrictions are not, shall we say, very palatable. What about, though, if we could address the problem without most of us even realising? What, Cameron Voisey is wondering, if it’s our environment that’s at fault, rather than us?

Cameron - Picture this: you’re tired, hungry and want some quick food. What do you go for? Some fruit perhaps or maybe a chocolate bar instead? Faced with these choices, opting for the healthier one can be hard. But what if our environment was changed, just a little bit, to make healthier choices easier? Could this make a difference?

James - One of the main factors that’s causing this sudden rise in obesity and overweight rates are the unhealthy food environments that surround us

Cameron - That’s James Reynolds from Aston University, whose new research studied minor modifications to 19 workplace canteens. They found that swapping out a few high calorie options with lower calorie alternatives - say a beef burger with a chicken burger - and slightly reducing the portion sizes of the more calorific products, resulted in a 12% decrease in the workers’ calorie intake while at work. Importantly, these weren’t sweeping changes across the whole canteen - only some of the items were altered - but combining small changes can make a big difference

James - This project evaluated two different interventions and we found evidence that adding one to another was much more effective than an intervention in isolation. And there’s every reason to believe that this would continue to be the case with other interventions that are combined to it

Cameron - Similar changes, or ‘nudges’, have also been looked at in supermarkets. Research from the University of Southampton and Deakin University found that a set of simple modifications - like placing fresh fruit and veg by store entrances and removing confectionery from near checkouts - could have a big impact, resulting in around 10,000 extra portions of fruit and veg and 1,500 fewer portions of confectionery being sold per week per store. The same products were there, just in different places. Helen Brown from the Behavioural Insights Team, who was not involved in the study, explained why these findings are so important

Helen - First, it shows the incredible potential of supermarkets to support consumers and make healthy choices really easy, at almost no cost to their bottom line, which is obviously critical for retailers and manufacturers. I think what’s most exciting though is that these interventions were trialled in discount supermarkets, located in economically deprived neighbourhoods. Now, this is really important as we know that obesity and poor diet is socio-economically patterned, and so research in areas of lower income is much, much needed. And I think that’s really what is very exciting about this work

Cameron - But from a behavioural point of view, where does all this come from? Are we really just victims of our environments? James again

James - There is an old view in Psychology that a lot of human behaviour is entirely intention-based, that people do exactly what they intend to do all the time and that merely by changing people’s intentions to, say, eat fewer calories, that might be sufficient to help people lose weight or intend to do whatever else their goals are

Cameron - But, as James told me, these ideas are quickly becoming outdated, as a growing body of evidence suggests that there are so many more factors that play a role in our decision-making – our environment being a prime example, as Helen explained

Helen - So according to dual-process models in behavioural sciences, there are two systems which drive human behaviour. The first is the reflective system, and this system is all about our rational and analytical processes. So for example, if we take lunch time – if we were using our reflective system, we would stop and think carefully about the pros and cons of all the different food options available to us. Now, obviously, using this reflective system is effortful and requires lots of cognitive resources, and so in reality, much of our behaviours are driven by the other system: our automatic system. And our automatic reactions to external cues from the physical and social environments in which we live, work and play therefore become really critical and sometimes lead us to make unhealthy choices. Now what’s really tricky is that our reliance on this automatic system is heightened when we are tired, busy, hungry, distracted, and that’s why it’s so critical that our environment makes it incredibly easy, if not the default, to make the healthy choice

Cameron - But there is hope for the future

Helen - There is a whole suite of interventions we can use to really shape the environment in which we are shopping, both online and in store, to ensure that the healthy option is absolutely the easiest, the quickest and really supports us in making good choices

Well the easy option sounds pretty good to me. That was Cameron Voisey. He was speaking to James Reynolds and also Helen Brown, and both of the papers that they were talking about have just been published in the journal PLOS Medicine.

Arguably, one of the key questions about the menopause is when this will happen to an individual - knowing that would take a huge weight off many couples shoulders, because it would help them to plan better when to start a family. A major determinant is down to the genes you carry as a recent, very large study published in the journal Nature has shown. Chris spoke with one of the team behind that work, Cambridge University Obstetrician, Catherine Aiken...

Catherine - We looked at millions of genetic variants across hundreds of thousands of women - there are over 13 million places in the genome where you can have variations in your genetic code. And when we looked at how those were linked to age at menopause, we could identify nearly 300 independent signals within the genes that could explain a large amount of the variation in the age at which women were going through the menopause naturally.

Chris - How did you gain access to so much information about so many people?

Catherine - These are databases available to scientists worldwide to study problems exactly like this, where you need an enormous number of people to be able to sift through so many tiny, tiny, tiny little pieces of the genetic code. The trouble is that there's so much variation naturally in the genes of different people. And so you need an awful lot of women to add together, to be able to predict with any kind of accuracy when somebody would go through the menopause.

Chris - I see. So you've basically got a massive, great group of women. And you're able to ask in this group, are there any parts of the genome that keep cropping up as different in relation to how their age at menopause changes? So you can see there's a sort of link there between that bit of the genome changing in a certain way and the age of menopause changing in the same direction each time.

Catherine - That's right. And we find nearly 300 different places across the genes where that is true. Some of those have a very strong effect, and in other places the effect size is less. But when you add up all those tiny, tiny variations, you find that you actually get quite a powerful effect on your age at menopause. Normally when we think of genetics, we think of a single gene changing and that having a profound effect on whether an individual has a medical condition or not. But in this case, what we find is that there's no single gene. It's a very subtle effect of lots and lots of genes added up. And that's why age at menopause has traditionally been so difficult to predict and why it's been very, very hard to know who's going to go through the menopause at 40 and who might still be premenopausal well into their 50s.

Chris - I suppose what one can do is to ask, well, now you've got those regions of the genome that seem to have this influence, what do those genes in those regions of the genome do? Because if you know what the genes do, that can give you some kind of insight into what the mechanism of an earlier or a later menopause might be.

Catherine - Yes, so that's really interesting. When we look at all those genes, a large, large number of them are connected with what's called the DNA damage response. Basically that's the biological system that makes sure that cells are maintained in their young and healthy state - it's the body's natural repair system. The trouble is that when the body's natural repair system isn't working so well, then that has a profound effect on the ovary. As we already heard, the eggs in the ovary are set before birth, and so it's even more important for eggs than other cells that they are well maintained and that the cells around them that support them are well maintained in terms of constantly repairing any damage, because those cells have been in the ovaries for so long - over 40 years in most cases. And so these genetic variants that we find are mainly to do with how well you can maintain and repair all the cells that support your eggs in your ovaries, which mean that they last longer, if you carry certain variants in those genes compared to others.

Chris - And if you know what those variants are, and you know that some seem to associate with better DNA repair and therefore longer lived eggs, and some seem to associate with a less powerful DNA repair process and therefore eggs that might wear out more quickly, does this mean we are now approaching a stage where we can make some kind of prediction about who might be at risk of an earlier menopause or even roughly when that menopause might happen?

Catherine - We're not quite there yet. We are absolutely approaching that and certainly this recent study gets us a whole big step closer to that. Before we did this study, we thought we knew about 15% of what contributed to somebody's age at menopause. This has taken us up to closer to 40%. It's still not good enough to use in a clinical setting for an individual person.

Chris - If it explains 40%, what's the other 60%?

Catherine - So there are probably genetic variants that we haven't found yet. We also know that there are lifestyle factors: alcohol consumption and tobacco smoking affect age at menopause. Those will all be additive and what we'll find is that there are certain things that interact with certain genetic variants, so smoking may be particularly bad for people who carry particular genetic links.

Chris - One other thing I'd like to pick up with you in this study, because you were finding genes that are linked to DNA damage and repair, and there are other diseases which are really profoundly tied up with DNA damage and repair, but also linked to hormones. I'm thinking, for example, some of the cancers, especially things like breast cancer. Was there any associations that you found in this study in terms of age of menopause and risk of those sorts of conditions?

Catherine - Yeah, absolutely. So the amount of data that we had - the biobanks that we use - are extremely well characterised. What we were able to do was then go back and look at women who had different combinations of genes and what their other health outcomes were. And that's really interesting to us because what we found was very strong associations between genetic patterns that predicted early menopause and genetic patterns that predict other diseases. What we found was that for women whose age at natural menopause was predicted to be later, their risk of several types of cancer increased, and those are the particular types of cancer that we know are linked to hormones. That really was exciting for us because it validates that connection between the genetic pathways that are causing age at menopause and how that interacts with a woman's health globally. So her risk of breast cancer, her risk of ovarian cancer, and then other things like type two diabetes and so on, that are clearly bound up, not only with genetics, but also with the hormonal effects of the menopause and so on.

The menopause may produce many symptoms such as disturbed sleep and hot flushes, as well as other health consequences such as osteoporosis. What can we do to combat some of these issues? Gynaecologist and founder of the publication Menopause Matters, Heather Currie, talked with Adam Murphy...

Adam - What options are available for women who are beginning to experience the menopause?

Heather - The first option, which all women need to know about and can continue addressing are diet and lifestyle issues. And as we heard from Juliet, this can have an impact on bone health, but also cutting down smoking, cutting down alcohol, cutting down caffeine, maintain a healthy diet and plenty of exercise can also help those early menopausal symptoms that we heard Imogen talk about. In practice though, many women may be really struggling with symptoms and may not be in the right mindset to change their diet and lifestyle. And often we do need to help them get symptoms under control, but then continue to advise and encourage about the diet and lifestyle changes. The most effective treatment is hormone replacement therapy, and it really does what it says on the tin. It replaces the hormone. We've heard that the consequences of menopause, both the early symptoms, the intermediate symptoms, which are related to vagina and bladder problems, and also long-term symptoms such as changes in bone health are all due to lack of oestrogen.

Heather - And therefore what HRT aims to do is give the oestrogen back. There are many ways that oestrogen can be taken. It can be taken in a daily tablet, a twice weekly patch, a weekly patch, a daily gel that you apply to your thighs or to your arms, and a spray, which is the newest option, which you can apply to your arm. So the main part is oestrogen. And as we've heard there's oestrogen effects throughout the body, and when it gets into the circulation, it goes around the body and helps those effects that we've heard about. Unless someone has had their womb removed, i.e. had a hysterectomy, then the other hormone that's involved is progestogen. So this is needed to prevent oestrogen stimulating the lining of the womb, which if went on for long enough could increase the risk of thickening of the lining and in fact, endometrial cancer. But we have ways of combining the progestogen which can be really simple, such as within the daily tablet or within a patch, or can be taken as a separate option along with your separate oestrogen. So there's lots of options to think about. And it's really important that women take time to get the information and find out what's going to be best for them.

Adam - And when we're talking about any kind of treatment, any kind of therapy, there are side effects. As Catherine mentioned, there's a higher risk of breast cancer if the hormones stay in the system longer. Does that kind of thing apply here to HRT as well?

Heather - There is an association with a small increased risk of breast cancer in certain types of HRT. So if a woman is able to take the oestrogen-only - as I said, that's only relevant if she's had a hysterectomy, had the womb removed - then there seems to be little or no risk of an increased risk of breast cancer. However, if the oestrogen is combined with progestogen, then certain types of HRT taken for more than five years after the age of 50 may be associated with the stimulation of breast cancer cells that are already present, not actually causing the breast cells to turn into cancer. So perception of risk is really important and really complicated. So if one woman is having minimal menopausal symptoms and knows of someone close to her who had breast cancer, then she's going to be more concerned about the breast cancer risk than the benefits from HRT. Whereas another woman who doesn't have any sort of close history of breast cancer and is having significant symptoms then for her, there's going to be far more benefits by taking HRT, but overall for the majority of women under the age of 60 or within 10 years of the menopause who are having menopausal symptoms and may have risk factors for bone health, or may just have the risk factors for bone health, the benefits of HRT far outweigh the risks.