Hormones
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Hello. At any moment of the day, throughout our lives, our bodies are producing chemical signals that are sent to other parts of the body. We call these chemicals hormones, and we produce more than 80 of them, of which the best known are arguably estrogen, testosterone, adrenaline, insulin, and cortisol.

On the whole, we don't notice hormones as their goal is homeostasis, keeping the levels of everything in the body as they are meant to be. But their actions are vital for our health and well-being and influence many different aspects of the way our bodies work. With me to discuss hormones are Andrew Bicknell, Associate Professor in the School of Biological Sciences at the University of Reading,

Rebecca Reynolds, Professor of Metabolic Medicine at the University of Edinburgh, and Sadaf Farooqi, Professor of Metabolism and Medicine at the University of Cambridge. Sadaf, what are hormones?

So hormones are effectively proteins which are made by one particular gland in the body and then circulate in the bloodstream to go and act on another different site. And effectively they coordinate all of our physiology and they allow us to do very fundamental things such as metabolize the food we eat to grow and to reproduce. And our hormones even control our immune system.

Is there any way to explain to the listener what a hormone looks like? I mean, they have slightly different shapes, but they are sort of often proteins, so small molecules, but they go and they act on receptors. So they effectively dock onto receptors. And then that process of docking onto a receptor triggers a chain reaction, which then regulates the switching on of genes or the sending of signals inside a cell.

So if you imagine almost like a bit of a spacecraft or something travelling around a highway and then docking in at a certain position. So receptors take many different shapes and sizes, but they're often very particular to receive the signal from a specific hormone. And they're really shaped so that the hormone can fit precisely into the receptor, and then when it does so, it triggers a response in that particular cell in the body. How are they produced, and in what particular part of the body are they produced?

So the hormones are produced by many different endocrine glands. So it's a gland that knows how to make hormones, basically package them up into small packets and then release them on cue into the bloodstream. So for example, the thyroid gland or the ovary or the testis. But also those particular cells that have the machinery to make the hormones are also found in our gut and actually even in our fat cells. So there are a lot of different cells in parts of the body that have the capabilities to make hormones.

They make many different hormones. So you always have the same set of genes within a cell, but a particular cell will have a certain function, and that means that it switches on or it makes or produces a particular hormone, and that fits with its overall function. So the thyroid gland mainly focuses on making thyroid hormones. You don't tend to make them in the ovary, for example. So you have a specific recipe, if you like, for making the hormones that are then released into the bloodstream. All species have...

hormones or hormone-like molecules. So flies have them, worms have them, mice have them, all kinds of animal species have these hormones. And they play very fundamental signals because you've always needed to have a system to coordinate your behaviour and your physiology. And that's essentially what our hormones do. The more and more I do this programme over the last many years...

There seems to be a factory inside all of us, a very skillful, advanced, developed, fine-crafted factory. Very much so. And I think that's exactly what our hormones are actually, the conductors of an orchestra. They're effectively the system that pulls everything together and makes sure that everything is acting in concert and at the right time. Thank you. Andrew Bicknell, how does the body know when to release?

hormones. So in your introduction, you mentioned this idea of homeostasis, this idea that we sort of stay the same. So much of the endocrine system is regulated by the fact that something changes and it needs to be corrected. So to give you an example, when we eat something, our food goes into our stomachs and then into our guts where we absorb the nutrients and the levels of glucose will rise in our blood.

And that rise in that level of glucose needs to be sensed or is sensed. And we release insulin into our circulation, into our blood that travels around the body and it binds to its specific receptors, which encourage the cells to take up that glucose and store it. And it gets taken up into fat, into the liver and into muscle.

So by doing so, the glucose level will then begin to begin to lower and it returns back to where its set point is. So most of most hormones are produced in response to something changing and returns that whatever that level is back to where it should come from.

I'm fascinated by these receptors. I mean, they're just lying there waiting for something to happen and then they can grab it and use it. Yeah, that's exactly it. And this is the wonderful thing, I think, about the endocrine system in itself. The gland, the endocrine gland, releases the hormone into the blood and that travels all the way around the body. And every cell and tissue will see that hormone, but it only acts on a few of those tissues or it might act on many of them. And the way that it does that is because the cells...

that respond to the hormone, effectively they express, they produce the receptor that the hormone binds to. So I think a really good analogy to that might be the idea if you think of the hormone as a key and you're walking down a street and there's all these doors with locks in it and all of a sudden you keep trying the key and all the locks until you find the one that it fits and the door opens. Extraordinary, isn't it? It is amazing.

Do you have any idea when this developed and how it developed? The early part of the endocrine system, or hormones per se, the first molecules are more like steroid molecules rather than the peptides and proteins that were mentioned earlier. There are examples of these even in bacteria, but not in the same sort of light. They're sort of signalling molecules which, again, sense things in the environment and cause a response. Rebecca Reynolds, I...

What's the significance of the pituitary gland and the hypothalamus? Yes, so the pituitary gland and the hypothalamus are really the key regulators and the key controllers, if you like, of the way the hormone system works. In fact, we call the pituitary gland the conductor of the endocrine orchestra because it's really there, got a vital critical role in coordinating hormones.

So the hypothalamus is a small part of the brain and what it does is it receives signals from various parts of the brain, from the nervous system, from other tissues and then integrates those signals and then sends signals to the pituitary gland in the form of releasing hormones or inhibitory hormones.

And this then tells the pituitary to produce other hormones. The pituitary's got two parts. The anterior part of the pituitary produces these stimulating hormones, which then go out in the bloodstream to all the different glands that we've just been talking about to make those individual glands release their hormones. And the back part of the pituitary actually releases stored parts of chemicals that the hypothalamus has made, which regulate our salt and water balance.

So it's a bit like a thermostat running a central heating system in the way that they talk to each other. So if we think of the hormones circulating around in the body as like the room temperature...

If they go up too high, then the signals from the pituitary and the hypothalamus will get switched down, like the thermostat, and then vice versa. If the temperature goes down or the hormones go down, then the pituitary and the hypothalamus will switch up to make more hormones be produced. You've talked about them in the brain. Do you know where they're situated in the brain and why they're situated and where they're situated? So the hypothalamus is in what we call the higher centres of the brain, below an area of the brain that we call the thalamus.

And then it's anatomically located just above the pituitary gland, which is a pea-sized gland that's really almost just behind the back of your nose at the very base of the brain. And they're so tiny to do all this business. They're very small, but they're packed full of lots of different cells which can release these different signals.

Do they link in with other systems in the body? Absolutely. So the hormone system or the endocrine system is really tightly linked in with almost all our different systems in the body, particularly with our metabolism, with our reproductive system, with our nervous system and our immune system. And I guess we see this most when one of the hormones goes wrong.

So, for example, if you develop an overactive thyroid and you're producing too much thyroid hormone, you have symptoms in virtually all parts of your body. So your metabolism goes into overdrive. You feel really hungry. You eat a lot, but you lose weight. Your nervous system gets stimulated, so you feel really shaky. Your heart races too fast. You can't sleep at night. And then your temperature regulation goes out of kilter, so you feel very, very hot.

And then we see the opposite if that thyroid gland is underactive, so you've become very tired and sluggish, you gain weight, you feel really cold. And so you can see that even though it's just one hormone that's gone wrong, it's affecting lots of different parts of the body and lots of different systems. But then central control moves in and corrects that. So that's what tries to happen. But in disease, then sometimes the system is so switched on or switched off that the central control cannot manage to overcome those changes. What strikes me is how efficient it seems to be.

I guess it's regulated a second-by-second or a minute-by-minute system, and so some hormones take a little bit longer to regulate, whereas others can be changed very quickly. And it's extremely intricate. The regulation of the hormone system is very conserved between species, so you'll have a very similar response in a different setting or a different animal, but the actual underlying mechanism will be very similar.

Thank you. So now it's a huge system and we have time to look at some of it. Let's talk about food, which most people know about. Can you tell us how hormones impact on the intake of food, etc.? Yes, we've learned really quite a lot about this in the last 20 years. So it's quite a recent understanding that we have. And what we now know is that

Actually, how much we eat, what we eat and how rewarding or how much we crave food is strongly influenced by our hormones.

And so those hormones come from our fat, for example. So we used to think that our fat tissue was just there to store extra calories. But actually our fat can make hormones. One of them is called leptin. We also make hormones from our gut and they're released directly with relation to meals. So when you eat a meal, depending upon where the food goes in the gut, certain hormones are released and they tell the brain about how full you are. And that sends a signal to end your meal or to end eating.

Are you able to ignore this? Of course, we can all recognize that sometimes we can override those signals. But it does explain why some people feel more full.

more easily than others, and other people can override it more easily. So yes, we can override it on a sort of a single attempt. But over time, generally speaking, those hormones will influence how much you tend to eat. And what's interesting is those hormones work in the brain. So that's where they send the signals from the gut, the fat, the liver, those other organs back to the brain, and the brain then has to put it all together.

Now, the brain circuits in the brain respond to those hormones, but they're the same circuits that are influenced by our environment. So if you read a nice menu or you go through a recipe or you see some advertising, what we don't realize is that those signals are taken into the brain and they act on those same circuits that our hormones are acting on. And that's partly how you can override that feeling of fullness if you happen to see a menu describing a very nice piece of cake at the end of your meal.

because you've actually got a part of the brain that's overriding some of those fullness signals. So it's not automatically and mechanistic. So there is an automatic element, but you can sometimes override it. Now what's tended to happen is because we can sometimes override it, we've tended to think that we can always override it and it's under our personal control. And actually that's something fundamental that we now understand is not true. It's a bit like breathing.

We breathe most of the time automatically without thinking about it. But occasionally, if I ask you to, you can hold your breath for a certain amount of time. You can voluntarily override the system.

But most of the time, you'll do what the system dictates you to do. Thank you. Andrew, it gets more and more fascinating, doesn't it? It is. What affects the length of time that hormones stay in the body? Okay, so there's different types of hormones. So we've talked a little bit about protein hormones and a little bit about steroid hormones. And there's

There's really three main types. There's these protein hormones, the steroid hormones, and there's also another one known as the modified amino acid. Those are the three main types.

And they do have different lengths of time that they exist in the body. So the protein hormones and the variant of the protein hormones, which we call peptide hormones, which are like very small proteins, they tend to be in the body for quite a short length of time. So what we call their half-life, so the time for half of it to disappear from the blood. And those are measured often in minutes to hours.

where some of the other molecules, the steroid molecules, they have much longer lives in the body, which often can be from hours to days, for example. And the way that this is regulated is the way that we actually get rid of our hormones. So the peptide and protein hormones are mainly broken down by the kidneys and by the liver. The steroid hormones are mainly broken down by the liver.

And often steroids, for example, they're bound up with other molecules that help them circulate in the body. And by doing so, that makes them last longer. So the peptide hormones, they tend to act very fast. So they have a very quick mode of action and then they disappeared. With those steroid hormones, their action tends to last much, much longer because they hang around for much, much longer. What are they made of?

So the protein and the peptide hormones are made of things called amino acids, which are the building blocks of proteins. And essentially we have genes which encode them, and there's a sequence of those amino acids. We have 20 naturally occurring amino acids that we find in proteins that make all of our proteins up. And the arrangement of those, the order of those, gives the hormone molecule its properties and also its shape. The steroid molecules, on the other hand, they're all made from cholesterol.

We often hear that cholesterol is bad for us and we shouldn't eat too much cholesterol, but it actually forms the precursor to these molecules. And all of the steroid molecules, things like testosterone and progesterone and estrogen and cortisol and so on, are all made from cholesterol. And they've got quite a common structure to them, but with some little modifications on the side of them.

And the other family of hormones, these modified amino acids and the thyroid hormones are probably one of the best examples of those. And also adrenaline is another example of a modified amino acid. This is where we take one of those amino acids and it's chemically changed and it has bits stuck on it to change its biological properties. And we have one particular amino acid called tyrosine, which is the one that's most often changed to make these amino acid hormones.

Rebecca, what are some of the significant differences that various hormones make during pregnancy and childbirth, for instance? So in pregnancy and childbirth, the mother undergoes huge hormonal changes. There's some really complex interactions between both the mother and the baby and also the placenta, which signals the different hormones between them.

We see classically as pregnancy progresses that many hormones rise in very dramatic levels. So things like insulin, cortisol, oestrogen, progesterone, they all rise during pregnancy. And the reason they're doing that is they're partly preparing the mother for the pregnancy. So laying down of food supplies, so storage of fat and then subsequent release of those nutrients to the baby so the baby grows faster.

and then also preparing the mother's body for the changes that happen during childbirth. And we know that these hormones are also really important in terms of the growth and development of the baby. So, for example, cortisol, which is a major stress hormone, that's really important for the baby's growth, but also important for the ways that various tissues and organs will mature.

But the mother has these really high levels and it's really important that the baby doesn't have too much of the hormone because otherwise it might actually cause problems. So the placenta has...

series of systems which means it acts like a gatekeeper to prevent the mother's hormones going over to the baby and it actually has an enzyme within the placenta that breaks down the active hormone and turns it into an inactive byproduct so it protects the baby. So this system is exquisitely regulated to ensure that the babies receive the correct amount of hormones which will then impact on their growth and development. What

Why do you think that sort of exquisite regulation comes from? I think because one of the reasons, if I may, why I think it's a fine art is that actually because just small variations make things go wrong. So you have to have a lot of controls to get it just right. So essentially, as we were talking a little bit about before, if you have too much or too little of some of these hormones, you get very fundamental problems. If it's the thyroid hormone, it happens very early, the brain doesn't develop properly.

children will have learning difficulties, they won't be able to walk. You get some very fundamental problems. So to avoid easily tripping over into too much or too little, you need to have a very fine system to control everything and keep it stable. And so I think what we've developed is essentially...

proteins that will carry and protect those hormones, as Andrew was describing. You've got proteins that will reduce it if it's a little bit too much, that will change the level depending upon your age or your puberty or pregnancy. So you need a fine-tuned system to keep everything, basically it's like a Ferrari, you have to keep everything in sync.

I keep being fascinated by how this occurred, this exogee system. So it will be an evolutionarily phenomenon. Some of the hormones that we've talked about, as I said, so leptin, the one that's made by fat, flies have an equivalent hormone telling a fly how much fat it has on board and if it has enough nutrients to survive. So you have something very fundamental for survival here.

So even a regular fly has that. So people have it, but then people have to have extra levels of control. So these things have evolved over time. And actually some of this we're only now discovering because we have better tools to measure the hormones and the other chemicals in the body that regulate them. So it came together slowly, but you've been discovering it rather slowly too. Well, I think collectively,

Collectively, we've discovered quite a few, I think. What's fascinating, though, now is that we are actually still finding there's a lot that we didn't know. Because of technological advances, we can now measure very low levels of hormones and we can measure the genes and we can actually measure them in every single cell in the body. That's something that we and others are doing right now. So we're opening up some of those closed doors and we're finding that actually there's an awful lot more that hormones can do and there are hormones that we didn't know about. Where's free will in all this?

So it really returns to the point that actually, of course, there is an element of free will, but many of the processes that we've talked about occur spontaneously and subconsciously. What do you mean by subconscious in this context? So, for example, we haven't talked yet about the flight fright response. No, we're coming to that. So we're coming to that. So that's a very fundamental response, right? You see something scary and you will feel fear and anxiety and you will immediately get an adrenaline rush.

and you will get a faster heart rate, your blood pressure will go up, you'll feel a bit sweaty. But that's so quick. That's not you saying, oh my goodness, I've seen something scary, I better get ready to run. It happens automatically the second you see something. So these things happen automatically before your conscious mind has time to tell you to do something. How does your conscious mind know that what's coming towards you is threatening?

So you receive these signals and they go into parts of the brain like the amygdala, for example. So the amygdala will respond pretty immediately. If you show somebody like a scary face...

Or if you show somebody snarling, for example, a photograph, in a second, you'll get a detector signal in your amygdala indicating fear. And that response to fear then communicates to the hypothalamus, which then sends a signal to the adrenal gland to release your hormones, your stress hormones. So it's a very, very fast electrical signal that then gets transmitted through these circuits leading to the release of these hormones.

Can I carry on with you about free will, Andrew? Why does free will figure? I mean, it's all happening because I see something that goes click and then it goes another click and another click and another click. It's nothing to do with me. No, well, we've evolved. These are very primitive responses and we have a whole system set up in us to effectively come back to this idea of homeostasis in a way. Of all these things, the whole system is just kept running and keeps going.

kept in check without us knowing anything's happening our blood pressure is regulated the amount of glucose we have in our blood is regulated exquisitely without us even knowing about it and in a way you know I guess that that allows our free will to be thinking of other things ultimately I think the bottom line is we're not as in control of things as we like to think we are yeah

And that happens for all kinds of things. So we think we're going to control how perhaps we may be able to control some elements of our behaviour at certain times. You might choose not to eat that extra slice of cake, even if you're getting a signal in your brain telling you that it's rewarding. But if you constantly get that signal, it gets quite hard to override it voluntarily.

So just because we can sometimes override doesn't mean we are always overriding. A lot of the time the system is just running. Can I just add something on to this? I think one of the things that I find fascinating about the system is that these molecules, these peptide protein hormones and cholesterol, the mechanisms by which our bodies produce them or different organisms produce them is being completely conserved.

Every organism, the way that, for example, peptide hormones are made, these small proteins, the way that they're made, the way that their genes encode those amino acid sequences and the way that those molecules that they make, the proteins are then produced and processed into these smaller peptides.

is the same in worms and flies as it is in us. So the same machinery, basically. Exactly the same machinery. And that is amazing, I think, which really shows you that this is a fundamental necessity for life, for successful life. Rebecca, throughout our lives, the levels of some hormones come and go. What bearing does it have on the discussion?

So I think this is, I think probably one of the really good examples of hormones that come and go through our lives are the sex steroids, so oestrogens and testosterone. We see a really good example when we go through puberty, when we get big surges of these hormones. They're needed, therefore, to help us go through puberty. So that transition from childhood to adulthood, the changes that happen in our bodies when that happens. But then also, you know,

With puberty and adolescence, then hormones get a bit of bad press because they're also associated with things like mood swings, with greasy skin, with development of spots. And then we see the same hormones, again, particularly in women...

When they go through the menopause, women's oestrogen levels fall off dramatically. And that then leads to a whole load of new different symptoms. So things like hot flushes and then the risk of bones becoming thin and risk of heart disease. So I think steroid hormones have such huge variation. Actually, they have less variation in men. They tend to be a bit more constant. Even in men, they have what we call a circadian rhythm. So they're higher in the morning and then lower at the end of the day. Do you know where that is? Why that is?

Again, that's controlled by the hypothalamus. There's lots of different complicated mechanisms by which these signals are varied. And we have these things called clock genes, which regulate the way that different hormones and other peptides and proteins in the body are released at different times of the day.

So now, can we go back to fight and flight, which is easy for me to cotton on to. Can you develop that a bit? Yes, so the flight-flight response is a very fundamental response. It's really about escaping from a dangerous situation or from a predator. How do you detect it? Do you smell it? Do you see it? All kinds of things. So you may see it, you may smell it, you may hear it, you may touch something. So absolutely any peripheral sensory signal can then send signals

ultimately a signal to the hypothalamus, which is that control centre that we talked about. And it has a direct link to what we call the autonomic nervous system, which is sympathetic and parasympathetic limbs. Effectively, you can think of them as the accelerator and the brake. And so the accelerator is a sympathetic system which is

basically turbo charges you to run away from this scary signal by releasing adrenaline. And it makes your heartbeat faster, your blood pressure, you breathe more quickly, you start to sweat, and that's your accelerator kicking in. You have a break, a natural break to oppose that, and that's the parasympathetic system. And then after the scary signal has gone or died down or you've run away from it, that will sort of ease in and slow everything down.

Now, we have this and all animals have this. It's very fundamental. And there's another sort of layer that comes in. If the stress continues, you would then bring on board cortisol as another hormone that gets released to help you deal with this frightening situation. How does it help?

So it helps by basically maintaining that sympathetic system, but it also starts to kick in and release energy so that you have enough energy reserves to deal with the situation. So it might make you want to eat more. It releases some of your nutrients so that you have enough energy for your muscles to run, for example. So we have a very strong setup to deal with flight or fright. And then what happens in the real world now, of course, is quite challenging, is that people

And commonly, people will trigger that response for things which may not be quite so threatening. So, for example, it may be perfectly reasonable to have that response if you're being threatened by an intruder. But getting that response because you're angry in a traffic jam is probably not necessary. But invariably, it's a physiological response to getting angry in the traffic jam.

And what happens is if we trigger that response relatively easily when the situation is not that threatening, that's when we perceive anxiety. Because it's the same thing. So basically you release all of those hormones and that hormones give you the feeling of a fast heart rate, breathing more quickly, feeling anxious. You feel aroused. You feel alert on edge. So that is a symptom that is perfectly reasonable if you're going to run away from a threat.

But if you're sitting in a traffic jam or you're stressed at home because of the family situation, then you perceive that as anxiety. Thank you very much. Andrew, is it possible to synthesize hormones for medicinal uses? Yeah, absolutely. We've been using hormones as medicine for many, many years. The first molecules were artificially synthesized really in the 1930s, which were some of the steroid hormones, which was one of the first things that were made in the lab.

Probably some of the first therapeutic protein hormone probably used was insulin in the early 20s, mid-20s. What happened there is that the Canadians, Banton and Best, discovered the insulin molecule and they realised that you could treat people with type 1 diabetes.

In those cases, they had no source for a lab source of insulin, but they realised that you could extract it from animal tissue, so, for example, from a pig pancreas, and it works perfectly well in humans. And this is one of the things we mentioned earlier about how conserved, what we call conserved, the idea that these hormones are very, very similar. And some of the first therapy that was used was from these purified hormones from animals.

In later years, some of the hormones are very species-specific, so they only work in humans, for example, and one of those is growth hormone. And the first treatment of people who suffered from a lack of growth hormone really started in the late 1950s.

And we had to purify it from, in that case, from human pituitaries. And there were some health problems that came along with that. Unfortunately, although these preps might have been free from bacteria and viruses, they contained what was known then as slow viruses, which some people might have heard of Creutzfeldt-Jakob disease or CJD and the

the mad cow BSE, which is the underlying protein that causes those conditions. And some of these preps actually had those in them, these proteins, which unfortunately some of the people that were treated with those hormones actually developed CJD a little bit later life.

So what's then happened is that we've started producing some of these hormones in bacteria. So we could take the gene that encodes the protein sequence and we put them into bacteria and they will produce the protein molecule, which we can then take from the bacteria and use them to treat us. So things like, for example, growth hormone and insulin, for example, are all produced in bacteria now. So they're all synthetic and they're obviously free from all those problems that used to happen. All those problems, yes. Yeah.

What opinion do you have, Rebecca, on these synthetic hormones? Well, we use these hormones for treating endocrine problems, so hormone problems. Hormones to treat hormones? Hormones to treat hormones. Yes, hormones to treat hormones that are lacking or missing. So when we're missing a hormone, sometimes that's a life-threatening condition.

So, for example, Andrew was just talking about type 1 diabetes. If people don't have insulin, then they're not able to survive. And so we can treat diabetes now with insulin. Another example would be people who don't make enough of stress hormones. And then we have to give them back synthetic stress hormones, which they need to take for the rest of their lives. And also they need to modify the doses if they're unwell, for example.

And then sometimes we use synthetic hormones to treat people who've just got symptoms, but it's not life-threatening. So an example would be giving women hormone replacement therapy if they've got very bad symptoms of the menopause, or giving men testosterone therapy if they've got low testosterone and have symptoms of erectile dysfunction or decreased libido.

And then we also use these synthetic hormones in examples where we're treating other conditions. So, for example, synthetic steroid hormones are very powerful at reducing inflammation. So we can use those and treat people who have autoimmune diseases or who have inflammatory conditions.

So those would be some examples. Do you have anything to add there? No, I think you came to a nice point there with many other conditions. And it's because the hormones control so much of our system that we can harness that power to treat many different conditions. So asthma and many other disorders, arthritis, can be treated because we can understand how the hormones regulate the inflammation or the immune system and then fine-tune that response.

What more would you like to know at this time in order to make your investigation more perfect? I think there are many, many conditions for which many conditions, many diseases that people suffer from, for which we have an incomplete understanding. And, you know, anybody who looks after people will know that there are many conditions for which we don't quite understand why something happens.

And that's because we have an incomplete understanding of how our hormones work on many different organs of the body at the same time. So we've talked about the classical ones and the things that we know, but there's an awful lot of things that we don't know, for example. What do we not know? So what we don't really know is we only know things if there's a big effect. What we don't know is what is the added contribution of lots of little effects around the body. Okay.

So, for example, if we talked about steroids as synthetic hormones that we might use to treat somebody with asthma, we've learnt when we treat people for a long period of time that it can have a bad effect on their bones, it can have an effect on their skin, on their hair. But there are probably quite a few other effects those treatments may be having, for example, on their mood, on their brain and other organs of the body that we just simply can't measure or quantify.

So it would be great if we had more sensitive tools to be able to understand, to measure hormone levels at a really small level and then to figure out what hormones are doing precisely in every cell, in every tissue and put that knowledge together to get an integrated map. Is that possible? It's coming. It's coming. I think what we're finding is that technological advances in many different fields are allowing us to understand some of that very, very detailed information

What we now need to do is basically scientists, doctors and others across disciplines need to put their heads together and build a more connected map. We tend to figure out one area at a time, but fundamentally to understand how hormones work, you have to link it together. And that's really, I think, what the challenge is now. What would the benefits be? I think the benefits can be huge, firstly for our scientific understanding, but particularly for many other problems that we're yet to be able to solve or to treat.

So I'm very excited about the potential that actually we're now moving into an era where we should have a much greater and more detailed understanding of how hormones work. And with that, I hope, an ability to treat many conditions and maybe even prevent some conditions because we know how they emerge. Andrew, there are chemicals in the environment which come into play here. Can you tell us about them?

Yeah, so it was appreciated many, many years ago, really back nearly to the birth of endocrinology as a discipline that you could, there were chemicals or there were factors in the environment which could affect our endocrine system. And back in the 1920s, it was realized that animals that were fed perhaps moldy feedstuff would start to have reproductive issues.

And it turns out that there are many, many chemicals, both natural and more predominantly man-made, which can interfere with our endocrine system. They essentially act like the natural hormones. They bind to the same receptors and they cause all sorts of problems. A lot of reproductive issues, for example, is one of them. Things, for example, with fibroblasts.

Fish in rivers, for example, were downstream of sewage works. They start to become female rather than male because of the steroids that are in the sewage. Some of those are coming from oral contraceptive pills, for example. There have been problems with alligators as well, having the same problems in America. Alligators are a problem from contraceptive pills? No, they essentially become feminized. They become female. What happens when they become female? Well, they can't reproduce. Right.

But there's been many, many chemicals in the environment which have been linked to all sorts of issues by effectively interfering with our endocrine system. And to be honest with you, we don't really know the long-term effects of that. We've got a long way to go on that. Rebecca? There's also quite a lot of interest in these so-called endocrine disruptors in pregnancy. We can find evidence that there's microparticles, microplastics in the placenta, in the cord blood, even getting into the baby...

We don't really know what they're doing. There's a lot of what we call association studies. So people have recorded how much microplastics people have been exposed to and then looked at pregnancy outcomes. But we still don't know whether it's a causal pathway yet. The microplastics is a whole new field, which is really, I think, quite worrying, actually, because we're finding them turning up in places all over our bodies, in our brains.

I don't think we really fully understand the effects of all the chemicals that we are exposed to every day in the environment, which we have no choice but to be exposed to. They come through our water, through our food, through what we breathe. And I say this has all really come about since the beginning of the industrial age. And it is quite hard. And I think the reason that you were a little cautious about estimating the scale of the problem is that because we don't know yet the scale of the problem because we haven't been able to measure it.

So it's very hard to pinpoint. You gave some examples that we can pinpoint, but there's probably quite a few things where it's hard to measure that this particular chemical in that environment

or exposure in the environment caused this particular problem. But there's already several examples that we can prove. And so the potential is really that we need to really quite rapidly understand how these things work. But one of the major ways they're going to be doing these different things is by mimicking the effect of the natural hormones that we have in the body. So where do you think... Is there a next big move, Rebecca, about hormones? So I guess it would be...

probably in the next few years we will see big advances in the way that we can treat hormone problems and the way that hormones can be better tailored to individuals. I think what we've been talking about, what we've really highlighted is that the endocrine system or the hormone system is very, very tightly regulated and very, very complex. And so therefore our current treatments that we use are

go quite a long way from mimicking that. We know that we're starting to get a little bit better, so we do have some drugs, for example, that can now be modified in the way that they're released so that we can have higher levels in the morning and lower levels in the evening to more closely mimic what goes on in humans.

But we've also maybe got other ways where technologies can also help. And for example, artificial intelligence and machine learning. We've come a long way with the delivery of insulin, which used to be delivered through big syringes intermittently throughout the day, rather than responding to the day minute by minute or second by second fluctuations in the body. So we can now have very clever technologies.

glucose sensors which talk to the insulin pump via an algorithm meaning that levels of insulin can be really varied second to second so I think that's probably a way that will develop with other systems going forward and as we were talking about earlier with more detailed tools that we have so more ability to do genomics

then hopefully we'll be able to much more personalise these treatments and really tailor them for the individual in a precise way. Yeah, I mean, I think I'm very excited about learning more about how these hormones are working in every single cell, in every single tissue in the body and how it all comes together. I mean, that's a big question, but I think we are making some pretty big advances. In the next few years, I think we will really take a big step forward in our understanding in those areas. The moment that takes us to it.

And I think that will take us to a better understanding for treatment, but also for prevention of conditions and diseases. And we'll start to learn about, it will give us a framework on which we can then build the other things that we've talked about. So part of the challenge of understanding how chemicals in the environment affect health is that we've got too many unknowns. If you have a framework for understanding exactly how the hormones work together in every cell, then you can start to test that and say, OK, what's

How does a particular chemical in the environment affect multiple things? You can actually directly test that. So I think these kinds of advances will occur in fairly large steps now, driven by technological changes.

And finally, Andrew? Yeah, I'd agree. Technology drives science. It always has done. And this idea, as scientists, we tend to be very focused on our individual pet love, our own little system. And it's very easy to forget that it exists in a much bigger system. And I think the idea of trying to pull all the things together and understand all the different subtleties and how they actually work as a team, essentially, is really where the future lies.

And this comes back and coming back to the endocrine disruptors, the idea that, again, most of the studies that have been done on that are on individual chemicals. But, of course, we're exposed to a sea of these things. And it's then how do they all work together? What do they do as a group? And really...

The only way to understand that is to really understand how the endocrine system itself works as a group and as a team. Well, thank you all very much. Thank you, Sadaf Faruqi, Rebecca Reynolds and Andrew Bicknell and our studio engineer, Emma Hart. Next week, we'll be going down the rabbit hole with Lewis Carroll for Alice's Adventures in Wonderland. Thanks for listening.

And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Melvin and his guests.

A different topic indeed. Well, thank you very much, Gwenda. I'm afraid there's more work for you to do, if you don't mind. Quite a lot, I think. What didn't you have time to say that you'd like to have discussed? We didn't really talk about childhood. OK, so a lot of different... Hormones affect hugely a lot of critical things to do with early development, childhood...

how our brains work. There are... Fetal programming. Yeah, you know, conditions like autism, conditions that... hyperactivity. There are a lot of conditions which people wouldn't necessarily associate with hormones, which are reflecting changes in the chemicals in the brain, which work like hormones. Maybe that's a bit too far away, but these are kind of common things that people will have heard about and know about. Why don't we know as much about that as you would like to?

Again, it's been hard to measure and because it's hard to understand in detail what happens within the brain. But we are now beginning to realize that actually in the same way that we have hormones that go around the body and send signals to multiple different big organs, we have small hormones or signals like neuropeptides, small ones that travel within the brain and actually communicate changes within the brain.

And so you can effectively have a hormone that affects your mood. It can affect your levels of agitation or aggression. It can keep you calm. So quite a lot of subtle aspects of our behaviour...

that we've tended to think, again, maybe under voluntary control, are strongly influenced by our hormones. You mentioned actually about teenagers and mood swings in relation to the menstrual cycle, in relation to pregnancy. Of course, there are many effects. But people anecdotally know about hormones and mood. But actually, there's a whole area of behavior that is modified by our hormones. Rebecca, you were being pointed at, then. Yeah.

Yeah, I mean, I guess that one of the things that we also know that we didn't really talk about is the way that hormones can influence the development of the baby during pregnancy. But then that can then have lifelong effects on the way that it grows and develops. So it can signal its risk of getting diabetes in later life and getting high blood pressure and getting cardiovascular disease. We don't really understand exactly how that works, but it's certainly set up

in pregnancy when the baby's still in the womb. I had potentially thought about talking about when we were talking about synthetic hormones and the use of synthetic hormones that we are actually doing a current trial that is funded by the NIHR where we're looking at whether these synthetic steroid hormones might have benefits for women who have twin pregnancies. So

Whilst we know that steroid hormones have lots of different effects, there's still categories where we have actually very limited understanding and that's why we're trying to do this very large multi-centre randomised controlled trial, inviting pregnant women with twin pregnancies to take either the synthetic hormone or to take a placebo, so a dummy type of treatment, and then to follow up the children to see the impact that it has on the twins and whether they need to go to the neonatal unit, which can sometimes be a complication of twin pregnancy.

Yeah, I guess one sort of area that we didn't really talk about, we talked a bit about hormones and food and also the sensation of fullness and driving appetite is, of course, this new generation of medications for the treatment of obesity and for weight loss, which are receiving a lot of attention. They work by effectively acting on those hormone receptors.

So the reason that those medications work is they're effectively telling the brain that you're full and you therefore want to eat less and therefore you lose weight. So essentially those medications are harnessing the hormone system that we have. How do they work on the receptors? So they basically dock on to those same receptors. So they basically mimic the hormone and they dock on.

onto the receptor and they trigger fullness response. So you feel full, you don't want to eat so much, you often don't even desire appetizing food that much. And that's why then people lose weight. So it's an example of how treatments can harness the hormone system to effectively treat conditions such as obesity and diabetes.

And they have really dramatic effects on weight loss as well. So people will lose significant amounts of weight. But interestingly, as soon as they stop taking the treatments, the weight goes back on. Which makes complete sense from what we were talking about at the very beginning, because it's a homeostasis system. It's a hormone system. So you perturb in one direction, the body will trigger a set of responses to restore you to an even keel.

It depends what even is. It depends what even is. And so that relates to this concept, which we didn't quite name, but you alluded to a little bit, Andrew, was of set point. So at the beginning, we talked about homeostasis, which is keeping what even is, is balanced. And we generally have a very precise set point for certain things like temperature. So if you get too hot, you will sweat. If you get too cold, you will shiver. And you're doing these things to restore your set point to normal.

We do actually have a set point for weight, which then is surprising. How come everybody's not a perfect weight? Well, actually, probably in reality, we have like a set point range, right?

And different people have a different set point naturally, and that's influenced by our genes. And one thing that we didn't talk about is actually our genes will strongly influence all of our hormones. And so the level of a particular hormone you may have is not a single number. It's often a range. And where you lie in that range will be influenced by many things. But one of the big things is your genes. So some people who are naturally more likely to be heavy naturally

will naturally have a higher set point for their weight. Whereas there are other people who can eat what they like and they stay slim, they naturally have a lower set point. And the same will actually happen for quite a few different other hormone systems in the body. Yeah, I think the point is, is coming back to weight, that there's an evolutionary advantage. If you're, if we're used to eating every day, you know, regular meals and so on. But of course, you know, in nature, that's not really the case. You know, you might actually have to, you

You know, you have a meal, you kill something or whatever it might be, and you eat as much as you can. And then you go for a period of not eating at all because while you're trying to find the next meal, you know, and of course, we're evolved. It's an evolutionary advantage to us to manage to eat as much of that in one go as you can because you don't know when the next meal is coming. And, you know, that persists with us now. And it's useful to be able to store it. And it's useful to be able to store it, yes. Where, you know, perhaps if you don't do it, it's not such an advantage anymore.

to you when you don't know where your next meal's coming from. Well, thank you all very much. That really was fascinating. Thank you very much indeed. Great. Thank you. Thank you. It's good we came back to set point in home estate. Yeah, it's OK. Would anyone like a tea or coffee? Melvin, do you want a tea? I'd like a cup of tea, yes, please. Cup of tea, please. I'd love a cup of tea. Yeah. With a big whiskey. That's fine, thank you. Thank you so much. With a big whiskey and it would be good.

The Post Office Horizon scandal has shocked Britain. Post Office IT scandal, which has had so much publicity, hasn't it, over the last... This is a scandal of historic proportions. I've been following the story for more than a decade, hearing about the suffering of sub-postmasters like Joe Hamilton and Alan Bates. It was just horrendous. The whole thing was horrendous. I was told you can't afford to take on post office. And about their extraordinary fight for justice.

What was motivating you? Well, it was wrong what they did. Listen to the true story firsthand from the people who lived it in The Great Post Office Trial from BBC Radio 4 with me, Nick Wallace. Subscribe on BBC Sounds. Yoga is more than just exercise. It's the spiritual practice that millions swear by.

And in 2017, Miranda, a university tutor from London, joins a yoga school that promises profound transformation. It felt a really safe and welcoming space. After the yoga classes, I felt amazing. But soon, that calm, welcoming atmosphere leads to something far darker, a journey that leads to allegations of grooming, trafficking and exploitation across international borders. ♪

I don't have my passport, I don't have my phone, I don't have my bank cards, I have nothing. The passport being taken, the being in a house and not feeling like they can leave.

You just get sucked in so gradually.

And it's done so skillfully that you don't realize. And it's like this, the secret that's there. I wanted to believe that, you know, that...

Whatever they were doing, even if it seemed gross to me, was for some spiritual reason that I couldn't yet understand. Revealing the hidden secrets of a global yoga network. I feel that I have no other choice. The only thing I can do is to speak about this and to put my reputation and everything else on the line. I want truth and justice.

And for other people to not be hurt, for things to be different in the future. To bring it into the light and almost alchemise some of that evil stuff that went on and take back the power. World of Secrets, Season 6, The Bad Guru. Listen wherever you get your podcasts.