Welcome. We've been, over the last several videos, exploring some unusual types of ways of thinking about lactation. And we use this kind of terminology, non-puerperal lactation, lactation without giving birth. Normally we associate lactation, mammary growth and those kind of things with a female. But as we think about the definitions that we've used for here, for non-puerperal lactation, galactorrhea, for example, abnormal or spontaneous flow of milk from the breast, which is not associated with giving birth or with nursing. We think about other kinds of definitions we've had, mammogenesis, mammary development, or lactogenesis, initiation lactation. Galactopoiesis, the maintenance of lactation, mammary glands, all those kinds of things going back to all those kinds of definitions. No where near does it say that males can't lactate. So the question is, go to the next slide. Can males lactate? And hopefully you can already kind of tell the answer will be yes. And we want to kind of develop some ways of thinking about that and understanding that process in males. So let's go to the next slide. To do this we want to go back to thinking about our physiological processes that result in lactation. Mammary gland growth, so that suggests that there has to be some mammary tissue there. There has to be some amount of mammary epithelial cells. The cells that would differentiate into those lactocytes, the cells that are actually going to produce milk. And we also understand, we've already kind of given an example of where we know it doesn't take that much mammary tissue to do that. So let's go to the next slide, and it reminds you of this case of in our own species, which is milk. Newborn human infants, it occurs, again stimulated by maternal hormones when the infant is a fetus, before they're born. Once they're born, of course even though they've been exposed to those hormones. Of course the progesterone that's inhibiting lactogenesis drops, and so we start getting some colostrum-like secretion. Lasts for several days, or lasts maybe one to two weeks, and starts a few days postpartum. Clearly, in that infant there's very, very little mammary tissue there. But what tissue there is there, what epithelial cells there are there can respond to the hormones. They're potentially responsive to those same hormones that would be occurring in the mother in that case. So it doesn't take very much mammary tissue to potentially produce some sort of mammary secretion. In this case, it's usually described as more of a colostrum-like secretion. Let's go to the next slide. So we assume and we recognize that in most mammalian species the male has mammary tissue, it has nipples, it has teeth so it's going to have a little bit of mammary tissue. That's not the case in all mammalian species however, and we can point to some strains of male mice, where they do not have nipples. There is just no mammary tissue there whatsoever and so obviously they're not going to lactate. We know a little bit about how the process occurs. So I'll need to take you back to thinking about mammary development in the fetal stages, very early fetal stage. And so this would be the cross section through the fetus. Again this would be the surface here, there's a layer of ectodermal cells, recall ectodermal cells here, and then down here are going to be the mesodermal cells. Recall that the ectodermal cells start to congregate, and then as they congregate they sink down into the mesodermal tissue, forming this thing we call a mammary bud, and that's a fairly important stage of mammary development. So what happens in the male mice, is that this, go to the next slide. Literally this mammary bud is expelled from the surface of where the ectoderm is. Go to the next slide. And so after it's expelled, it's just sitting out here on top of this, and of course it's then going to degrade, because it's not going to continue to be maintained by the tissue. So in some male mice strains, there is no nipple, no mammary tissue, nothing. Also, in stallions, in male horses there is no nipple as well. We don't know the exact mechanism of that, it's probably something some what similar to this that we find in mice. Nevertheless in most species, in most species of mammals the males are going to have nipples, they're going to have some sort of mammary tissue there that could potentially be stimulated to produce some sort of mammary secretion. So we see that if there is mammary tissue there, those epithelial cells, they can potentially be stimulated, to stimulate to differentiate to potentially make some sort of mammary secretion, milk or something else, colostrum, whatever the case may be. So what stimulates them, we know that in terms of development, mammary growth, we especially estrogen and progesterone, especially estrogen we talked about that before is one of the key drivers of stimulating the tissue to grow. And we say well normally we think of in the male, we think of testosterone being the primary sex steroid with not so much estrogen. But let's go review a little bit here about steroid hormone biosynthesis and what we see is that all steroid hormone drive originally from cholesterol. To go down the pathway there are multiple steps between each of these that I don't have on here. We go through progesterone, progesterone is a precursor for testosterone. So normally in the testes, this is the pathway that's going to happen. But we also recognize that testosterone is actually a precursor of estradiol. So potentially in the male, this can go all the way into estradiol. I also pointed out as an aside here that cholesterol, remember the glucocorticoids, were involved in both lactogenesis as well as maintenance of lactation. And that's coming off here as well. But here, we're really talking about this pathway in this case. Let's go to the next slide. So normally in a male we think of this ratio of testosterone to estradiol as testosterone is the primary one of that ratio. So there's a lot more testosterone than estradiol. Go to the next slide. However, the situation can change where that ratio flips a little bit, where you have relatively less testosterone, relatively more estradiol, and that in males can result into what's called gynecomastia. So again, the abnormal development of the breast in that case. And that can occur in our own species in humans, or can occur in other species as well. Again, just going by the natural pathway here, if we get to switch the ratio of these two, we potentially can drive that mammary tissue into growing. And if it then grows, you have a bit more mammary tissue to be stimulated by other hormones, for example, prolactin. So if we go back to our expanded version of here, or what the primary regulators of these different physiological processes in the mammary gland are. We talked about estrogen, progesterone, well now we want to talk about prolactin a little bit. And recall that prolactin is very heavily involved both in mammary growth but also especially lactogenesis and then getting it to galactopoiesis and lactation function. Next slide. Where are the sources of prolactin? Placenta, well, males aren't pregnant so there is no placenta. So let's go ahead and go to next slide. We can just strike that one out. So that one we're not going to be concerned about in the male. On the other hand, certainly, in the male, pituitary, we can have this condition called hyperprolactinemia. Again, persistently or excessively elevated blood prolactin. In earlier videos we went through a whole series of kinds of things that might be causing, potentially contributing to this hyperprolactinemia. Various kinds of drugs, dopamine antagonists, anti-depressants, anti-hypertensives, etc., estrogens. We just talked about estrogen a half a moment ago there. Hypothalamic disorders, and we'll get back to prolactinomas. Again, just to remind you some of those kinds of things we talked about primary hypothyroidism in an earlier video. Neurogenic mechanisms that might be causing hyperprolactinemia, so persistent stimulus of the nerves, that the same kind of nerves that would be causing milk ejection, for example, remember oxytocin's a component that will cause prolactin release. And so, stimulation of nipples, breast or nipple stimulation. Chest lesions, chest surgeries, those kinds of things, potentially can cause an elevation of prolactin as kind of a side effect of that. And then, certainly, stress. Let's go to the next slide. Again just to remind you, again this idea of prolactinomas pituitary tumors. They're really the 40% of all pituitary tumors are a prolactinoma of one type or another, often leading to or causing persistent increase or elevated prolactin level in the blood. Again, this idea of women who have prolactinemia that is associated with pituitary tumors, very often have galactorrhea associated with that. Again, observed in both males and females, so again, males potentially can have prolactinomas causing galactorrhea as well. We're talking about different types of prolactinomas, the micro and the macro type. And again, how we might potentially treat those. So the same kind of things we talked about here and really kind of focusing more on the female, certainly can potentially happen in the male as well. So we see in that many of the kinds of things we've talked about and thought in the context of females in terms of sources of hormones that might stimulate the mammary development, might stimulate lactogenesis can potentially also occur in the male, depending upon circumstances. So it should not be unusual to think about the fact or the idea that males can lactate. There is one particular case I want to bring, just spend a few moments talking about and thinking about. Let's go to the next slide. If you go to the literature, if you go into the popular press literature particularly, what you're going to do is you're going to find, if you, for example look in say Google male lactation or something like that, you're going to come across something about male bats lactating. So very specifically, do male bats lactate? This all come back from one particular study done in the very early 1990s. Let's go to the next slide. It was studying a particular species of fruit bats, in Malaysia. And what they were doing is they were evaluating, it related to the species status on the endangered species list, and where it sits. They weren't endangered, but they were on that next rung down. And so they were trying to evaluate, what's the status of these particular kind of fruit bat, in this specific area? And so what they do, is they put mist nets up, these very fine nets, up in the tree canopy way up there, and the bats would fly in to it. They capture the bats, bring them down and then study and get kind of an estimate of the population how many males, females and so on and so forth, those kinds of things. Go to the next slide. They observed that in one area that they were collecting bats, that pretty much all of the male bats that they did collect had functional mammary glands. Now functional mammary glands in this case is defined as there was some secretion that they collected. So they could collect between four and six microliters, microliters, of some sort of secretion. They called it milk, but, they didn't really do any analysis on what the composition was. But there was a secretion from the glands. Thus compared to one of the lactating female bats, that was they were able to collect 350 microliters so about a third of a milliliter, third of a cc of secretion from the lactating female. So, that would presumably milk, so clearly these males were secreting a very very small fraction. A 1 to 2% of what you might find from a lactating female. So there was a secretion, we can potentially call it galactorrhea in that particular case. Histologically they looked at the mammary glands and found some similarities but also some differences compared to the lactating female glands. So there's clearly mammary tissue there. It looked relatively normal, there was some secretion from it. And so, we could say that, yes these males, at least had galactorrhea if maybe not lactation. So, what some people have talked about is that, this is part of their natural reproduction strategy. That the males might be then, feeding the young or nursing the young. And I'm not sure that very many of the young are going to survive off of that little bit of secretion. So I'm personally not so sure that that's what this is about, that there may be something else going on here in these animals. Go to the next slide. The other observation they made was that they collected in one or two other areas in Malaysia and none of the male bats there, had functional mammary glands. There's not a lot of really good evidence as this is a normal process in these animals, that perhaps something else was going on. Recall that they were being, evaluated in terms of their endangered species status. So that might suggest that there was some habitat shift. That there was some encroachment by humans for example and maybe their habitat was starting shift. Fruit bats are eating fruit. Many species of fruits, many types of fruits have phytoestrogen in them. So there's a range of other possibilities. We just don't really know what the cause of this was. Certainly, again, there was mammary development, yes. And some secretion from that. But whether this is a situation where this is part of their normal physiological process and they're actually nursing the young, that certainly to my knowledge has not been proven at all. So let's quickly review and just think about this again. Where you just go back to this way of thinking about what's going on in terms of lactation and the mammary gland, and so on and so forth. In males, we have to have some tissue. And again, with a very few exceptions, the males of most mammalian species are going to have tissue that can grow and potentially go through these other stages of mammary development and differentiation. In the male, we may find situations where we have potentially a shift in the ratio of estrogen and testosterone, so that we have enough estrogen there to cause mammary development that would then potentially lead in to these other physiological processes. Certainly, the male has a pituitary. It has potentially prolactin, potentially can have hyperprolactinemia. Again, from a variety of kinds of sources. So there's no particular reason to expect that males will not respond to elevated estrogen, whatever the source may be, elevated prolactin. And so, it should not be that surprising that males not only can lactate, but in some situations abnormal situations usually, in fact do lactate. So again, the punch line here is that, can males lactate? The answer is absolutely yes.