[SOUND] Let's continue talking about lactation. And we're going to focus now, we've been focusing a good bit on hormones. The systemic component of controlling lactation. But now we want to shift gears a little bit and talk about milk removal. But let's go to the first slide. Before we do that I need to remind you that relationship between systemic factors, hormones in particular. We use prolactin as kind of one of our best examples of what we're talking about here. These are typically stimulatory. We're going to get to the local factors here in just a moment. Autocrine factors, the feedback inhibitor of lactation, tend to be inhibitory. And so again, with this idea, this balance between these. And so as the gland fills with milk, when the gland is emptied with milk. We get this removal as a feedback inhibitor of lactation from the alveoli and the ducts that allows the gland to restart refilling. The hormones kind of pump it up and say, okay, let's get going. And so you have a heavy stimulatory effect. And over time as the gland fills up, get less of the stimulatory effect. More of a accumulation of feedback and inhibitor of lactation that slows down the milk secretion rate. Remove the milk again, boom, we're right back to where we started from. So we want to examine this part of the equation a little bit more and to see how that fits in. But before we do that, let's go to the next slide. Just to remind you, every time the animals suckle, every time we milk the cow, whatever the case may be. Again, we get milk removal, milk ejection, excuse me. We're talking about oxytocin surge, yes. But also, then, this prolactin surge. And again, that's one of our examples. But again, in another video just before this one in the sequence. We also talked about the fact that there were a number of other hormones that are increasing their secretion in response to the suckling or milking the animal. Again, we're going to focus on prolactin here as our key. But again that's happening associated with the actual act of removing the milk from the mammary gland. Let's go to the next slide. So we can think about that and think of it in a temporal manner in terms of over time. Again suckling and milking induced prolactin surge. So if we have a dairy cow that's milked three times a day. These yellow things kind of representing that three times during that 24-hour period. She's going to have a prolactin surge. On the other hand, we have a species like the sow where those piglets are nursing every 45 minutes to an hour or something like that. She's going to have many of these during the day. In fact, the prolactin level never really goes down to baseline between sucklings because it's going to last. It's going to kind of go like this, come down and then hit it again and so on, so prolactin stays up. If you take the piglets away from the sow, it takes maybe a couple of hours for this prolactin to go down to basal level. So clearly, there's going to be a difference between these kind of species in terms of this prolactin induced surge. And so we can think about what's happening in between these times when the gland is refilling. The next slide, so just to remind you of alveolar structure, the single layer of epithelial cells here around the lumen. And see some big fat droplets in the lumen here, there's another alveolus down here. Another one over there, there's a teeny part of one here, another one up here. We're going to focus on this one. And if we go to the next slide, what we find is that there is a chemical, it's still a little bit undefined as exactly what this is. It's probably several components that make up this functionality. We call this the feedback inhibitor of lactation, or F-I-L, FIL. And it's an autocrine factor or factors, and really what they do is they're produced as part of the normal part of milk production. So they're produced and secreted as a normal part of milk synthesis. So they're synthesized in the cell, secreted from the cell into the lumen. And as it accumulates in the lumen of the alveolus or the small ducts, it feeds right back on the same cell type. Remember, autocrine means it feeds back on itself. That is, it's secreted from cell type A, it feeds back and affects cell type A, whether it's the same cell or the cell next door. Or maybe some of the FIL that secreted from this one affects that cell up there, it's affecting the same cell type. Paracrine, paracrine means that it's secreted from this cell and maybe affects the stromal cell. Or something secreted from the stromal cell affects the epithelial cells, so it affects a different cell type. Endocrine means it's loading, it's going around from the blood from one tissue to another. Say from the hypothalamus or the pituitary, for example, down to the mammary gland or the ovary or something like that. This is an autocrine factor, an autocrine function. Go to next slide, and again, it seems to be at least involving low molecular weight peptides. And again the function is that it further reduces milk secretion. So as that feedback inhibitor of lactation accumulates in the lumen. As milk is produced and fills up this alveolar lumen or the small ducts. It's feeding back and continuously reducing further milk secretion. What that means is, well the other function before we go to what the ultimate meaning of that is. The other thing is occurring is as the gland fills, you also get an increase in intramammary pressure. And that's really affecting, it's not affecting secretion from the cells. The feedback inhibitor of lactation, the chemical is feeding back and reducing further milk secretion from the cells. We do get an increase in intramammary pressure, because of the filling up of the tissue with the milk. What we do see, though, is that that results in activating sympathetic nerves that then decrease the blood flow. So, for example, you have an arterial here, it's going to contract that a bit. Decreasing mammary blood flow in the tissue, decreasing the availability of hormones and nutrients. So that ultimately will impact further milk secretion. But the thing I want to emphasize here is the increase in intramammary pressure is not directly affecting secretion of milk components from the cells. It's not the fact that it's filling up like a balloon, it's a chemical feedback inhibitor of lactation that's feeding back on those cells. And that's what's reducing the further milk secretion from the cells. Milk product, milk secretion is self limiting, it doesn't go on forever. So if milk is not removed, if this feedback inhibitor of lactation that is the milk, because it's part of the milk, is not actually removed from the gland. Milk production's going to shut itself down. This makes a lot of sense because if a mother has a female. Whatever spaces you want to talk about, out in the wild, if the young die, she doesn't want to keep on producing milk. It's a very high metabolic drain on the animal. And so it makes a lot of sense from an evolutionary perspective that this would shut this functionality, would shut down very quickly. So, lactation shuts itself off, so it's self-limiting in that sense. And this is part of the mechanism for that, and it occurs at a local level. So in that sense it doesn't matter how much hormone and keep secreting all the prolactin you want. If milk is not removed the mammary gland is going to start involuting. It may slow down the process a little bit of involution or regression. But it's going to involute eventually because, again, it's self limiting. And that gets back to this local impact of of the feedback inhibitor of lactation. What happens then when milk is removed from the mammary gland? We get this stimulation of prolactin surge, so prolactin levels is increased, at least temporarily. Intramammary pressure is relieved so again the blood flows starts to be maximized. We reduced or removed this feedback inhibitor of lactation from the alveolar lumen, from the small ducts. And so those cells, they don't have that inhibitory effect right there with them anymore. And again, allows the gland to refill between lactations or between the milkings. So again, we get back to this idea. We've now kind of given you the foundation of thinking about the hormones. Beginning a foundation of thinking about the local factors and how these things fit together, and they are intertwined. So again every time we remove the milk, we're getting stimulation of this. As the gland fills gradually over time, this stimulatory effect wanes. We get a buildup of the feedback inhibitor of lactation that shuts down milk secretion, removing the milk. Boom, we're right back to where we started from. And we're going to examine this relationship a little bit more. Especially the impact of milk removal and how it kind of fits in with this in some subsequent videos. So let's do a quick review of what we've talked about here as we kind of get started talking about this idea of milk removal. Again, there must be milk removal to maintain lactation function. If you don't remove the milk it's going to shut itself off. There's a dynamic balance again this idea between the stimulatory or the systemic factors. Hormones can, prolactin being kind of our best example of that. Versus the local factors, feedback inhibitor of lactation being the best example of that. So it's a dynamic situation, so it changes over time between milk removals. Removing milk again stimulates release of hormones, prolactin in particular, but also other hormones, release of, removes inhibitory factors, that local factor. Decreases intramammary pressure allowing the blood flow to be maintained. And then eventually allows or, in total allows, the mammary gland to refill with milk, which is what we're after, getting to lactation.
