Hello, we're going to now start with the female reproductive system again, in this lecture, focusing on the hypothalamus-pituitary-gonad axis. And this is an image in a light microscope of three different forming oocytes in their follicles. So the oocytes are very large cells, and they're surrounded by cells that become what are called granulosa cells. These are very similar to the sertoli cells of the seminiferous tubules. And we'll see how they are going to play an important role in the differentiation or the maturation of the oocytes to prepare for ovulation. So this, again, is our common axis. And I want to point out how similar it is to what we discussed with the male where we're going to again have pulsatile release of GnRH from the hypothalamus. That's going to cause FSH, follicle stimulating hormone, and Luteinizing hormone, LH, to be released from the pituitary. So these two hormones are named for their actions in females. Remember that FSH acted on sertoli cells in the seminiferous tubules that were in contact with the developing sperm. So in the same way, FSH is acting on granulosa cells In the female gonad, the ovary, that are in direct contact with the forming oocyte. Those granulosa cells are also forming inhibin that is going to inhibit the release of FSH. Remember, the male LH was acting on Leydig cells, which were away from the sperm themselves, outside of the tubule. And in this case, LH is acting in a similar way on theca cells, which are outside of the granulosa cells. So they're not in direct contact with the developing germ cells, and remember that LH cause the Leydig cells to form testosterone, and it has the same effect with the theca cells. They're also going to make testosterone that the granulosa cells will convert to estrogen in a similar way that the sertoli cells converted some of the testosterone to estrogen as well in the male. So the similarities are really amazing. In the female, we'll be forming estrogen and at times progesterone that at most cases will be a negative feedback onto the pituitary and the hypothalamus to decrease FSH and LH production. However, there is going to be one time in each cycle where we're going to get a big increase of estrogen only. That is going to act to cause an increase in GnRH production, and in more specifically, LH production. And this to me is what's confusing about the female reproductive tract. So if you can just remember that there's this one exception. We have big increase in estrogen that's going to cause a big increase in LH. That will help you, and of course, we'll be explaining why and what the effects of this LH surge are going to be. So again, we're going to have local secretion of testosterone that's required for female and male germ cell development. And that we're going to have inhibins, they are going to decrease FSH production, and our sex hormones are going to regulate the hypothalamus and the pituitary. So very similar to the male. In the female, it gets a little confusing as well, because we've got an extra organ in there, the uterus. So we have the hypothalamus making GnRH affecting the pituitary, so it makes LH and FSH acting on the gonad. That's the same as in the male. The gonad is making estrogen, they're making sex hormones that are going to act on the hypothalamus and the pituitary. So this portion is just like the male. The confusing part is that we also have the uterus, but keep in mind that the uterus is only responding to the hormones that the ovary is producing. So the ovary is controlling the uterus. The hypothalamus and pituitary are not directly controlling the uterus, it's the ovary. So if you keep that in mind, I think that helps in terms of understanding why and how the uterus changes during the cycle, which is what we're going to focus on in the next session, not in this one. So let's compare the female germ cell production to the male where we said that the male, throughout his life basically, can make new germ cells. In the female, there's this is going to be big difference where a female is going to be born with her germ cells. So embryo germ cell production is going to happen during embryogenesis, it's just final maturation that's going to occur during the menstrual cycle. And a female is going to be born with millions of germ cells, of oocytes, okay? However, only several hundred are going to actually be ovulated throughout her life, because it's usually going to be one egg per month. And so this is where the female is not very efficient. Born with tons of germ cells but only a few hundred actually make it out of the ovary. In contrast, the male that makes tons of sperm, and they very easily can leave the reproductive tract, it's just that very few of them are going to actually fertilize an egg. We're going to now talk about what happens during oocyte maturation so that we're just going to lead to ovulation. The first part of oocyte maturation is going to be GNRH independent. So throughout the month, there are going to be follicles that are going mature up to a certain point without regard to what's happening with LH and FSH. However, the second part is going to be in response to LH and FSH. So in this follicle, which is this structure that contains the oocyte, so here's the oocyte. It's a very large cell, and it's surrounded by granulosa cells. These are similar to the sertoli cells that are surrounding forming sperm. And then, that structure is surrounded by theca cells, which are analogous to the Leydig cells of the male that are sitting outside of the seminiferous tubule. Also similar are their actions where the theca cells, like the Leydig cells, are the ones responding to LH, and they're also making testosterone. The granulosa cells, like the sertoli cells, are the ones that are responding to follicle stimulating hormone and converting testosterone made by the theca cells to estrogen. So you can see where this follicle stimulating hormone gets its name. It's acting on the cells that are in the follicle, so it's follicle stimulating hormone, and these cells are helping the oocyte mature. So as we get an increase in LH and FSH, we're going to induce at least a dozen different follicles to start to mature, to move from being a less mature state to a more mature state with a small increase in LH and FSH. That is going to stimulate the theca cells and granulosa cells so that they produce more estrogen. So this follicle will be producing more estrogen. Now, we said we've got at least a dozen follicles maturing, how do we ovulate only one? And so this is where we start a race, where we will have a chosen follicle that needs to do two things to win the race. One is that it needs to mature quickly so that it is producing lots of estrogen, and it will get larger and larger and have more granulosa cells and more theca cells, so that it will be able to produce more estrogen. At the same time, it is also going to increase the number of LH and FSH receptors so that the follicle will become more sensitive to those hormones. So we're having this positive feedback effect.where we are having FSH and LH being produced, causing estrogen to be produced. And that estrogen increases the number of LH and FSH receptors so that it becomes more sensitive to estrogen, which will then causes more estrogen to be produced. So this is one of the few times in the course where we're going to talk about a positive feedback effect, and this is going to be on estrogen increasing the numbers of receptors that then causes more hormone to be received to cause more estrogen to be made. So this one follicle that wins the race is large, producing lots of estrogen, and very sensitive to LH and FSH. It is now producing enough estrogen that it's going to act on the hypothalamus and pituitary and reduce LH, and particularly FSH production, which will then basically lead to the death of less mature follicles. Because the chosen follicle is still very sensitive to LH and FSH, because it's expressing so many receptors that, that dropping these hormones is not going to affect it, but it will affect less mature follicles. So in this way, we have a chosen follicle that has survived where it is making the estrogen that lowers LH and FSH but then can survive that drop, because it has so many receptors for them, and is very sensitive to those two hormones. So this follicle is then going to continue to mature even though FSH and LH are slightly reduced. The other follicles are now dying, this follicle is continuing to mature, and it makes a big amount of estrogen fairly quickly, and this is estrogen alone. This is now the stimulus that is unique in the female system that somehow causes an increase in GnRH production and then an increase, in particular, of LH production, luteinizing hormone. That increase in LH is called the LH surge. And it's what stimulates ovulation. So once the follicle gets big enough, it's making enough estrogen to cut the LH surge, which causes ovulation. However, we still have those granulosa cells and those theca cells that were making estrogen. That follicle that the egg just left and leaves behind collapses and forms what's called the corpus luteum, which is going to be a hormone-producing machine producing estrogen like it was before but also progesterone. So the effect of these LH surge are two-fold. It causes ovulation, that release of the egg, and causes corpus luteum formation. So this is basically the luteinizing effects of LH is to form the corpus luteum. So that's how it gets its name as the luteinizing hormone, and we'll see the role of the corpus luteum now that it's producing estrogen and progesterone. How can this happen in the female where now we have This LH surge in response to an increase in estrogen? And this is because the female brain is going to develop differently from the male brain. She's going to have the same collection of kisspeptin neurons that respond to estrogen or progesterone and cause a decrease in GnRH production. She has a second set of kisspeptin neurons that actually synapse to the cell bodies of the GnRH-producing neurons so that when there's that increase in estrogen, and increase in estrogen only, from that chosen follicle, that activates this kisspeptin neurons to produce a lot of kisspeptin. And that causes the GnRH-producing neurons to produce a lot of GnRH, and that causes the LH surge. So it's the second population of kisspeptin neurons that is somehow able to respond to that increase in estrogen only and cause the LH surge that's important for ovulation. This is just a summary of what we've been talking about where we have the ovary, that's outlined in gray here, and then we have the oviduct, which is the same thing as the fallopian tube that leads to the uterus. And we have immature germ cells here, or follicles that will undergo a GnRH-independent maturation. And we'll get this whole cohort that when we have a small increase in LH, and FSH are going to start to mature. Until finally, we've got now our chosen follicle that is producing lots of estrogen, which has decreased LH and FSH, which has then killed the other follicles. It's still surviving, because it's got lots of LH and FSH receptors, so its super sensitive to them. So even though even their amounts are lower, it's still able to survive. Now, it's going to continue to make estrogen and make enough that it is causing the LH surge. And that LH surge is going to lead to one ovulation. So here's the release of the oocyte and some of its granulosa cells into the fallopian tube or the oviduct. The second effect of LH is going to be corpus luteum formation, wwhich is what's shown in step five where now those granulosa cells and theca cells that remain are going to continue to do their job, respond to LH, and now not only produce estrogen but also progesterone. And that will remain, until finally about two weeks later, if there's no pregnancy, then this corpus luteum will degenerate. It will give up and say, okay, we haven't gotten pregnant, it's time to stop and start this thing all over. And so it will degenerate, meaning that then, estrogen and progesterone production will dramatically decrease, which is then going to be what leads to menstruation and the cycle beginning again. And we'll talk much more about that In the next session. So we've talked about how we've got this differentiation of germ cells that is going to happen in the gonad, as well as the formation of sex hormones ,and that's true for both the ovaries and the testes. And we've talked about how LH and FSH are going to have very, very similar roles in the male and the female, and then we're going to have this chosen follicle, but this is going to be the inefficient process in females is producing this chosen follicle. There's going to be many, many follicles that die for everyone that makes it through ovulation. The chosen follicle is going to make it, because it produces estrogen. That's going to increase its own sensitivity to LH and FSH and reduce the amount of FSH that's going to kill the less mature follicles leading to, usually, just one chosen follicle each cycle. And we're going to have this LH surge, which is hard to understand until you know that, it's because we have another group of kisspeptin neurons. They are going to respond to that sharp increase in estrogen that occurs because of the chosen follicle, and cause the LH surge, which will cause ovulation and corpus luteum formation.
