Hello, we're going to now start with the female reproductive system. Again, in this lecture, we will focus on the hypothalamus-pituitary-gonad axis. This is an image in a light microscope of three different forming oocytes in their follicles. The oocytes are very large cells. They're surrounded by cells that become what are called granulosa cells. These are very similar to the Sertoli cells of the seminiferous tubules. 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. This, again, is our common axis. I want to point out how similar it is to what we discussed with the male. 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. 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. In the same way, FSH is acting on granulosa cells In the female gonad, the ovary. They 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, in the male, LH was acting on Leydig cells, which were away from the sperm themselves, outside of the tubule. In the female, LH is acting in a similar way on theca cells, which are outside of the granulosa cells. The cells are not in direct contact with the developing germ cells. Remember that LH causes the Leydig cells to form testosterone. It has the same effect with the theca cells. They're also going to make testosterone. The granulosa cells will convert to the testosterone to estrogen in a similar way that the Sertoli cells converted some of the testosterone to estrogen in the male. The similarities are really amazing. In the female, we will be forming estrogen and at times progesterone. These hormones at most timess will be act as a negative feedback to 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 cause an increase in GnRH production, and more specifically, in LH production. This to me is what's confusing about the female reproductive tract. 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. Of course, we'll be explaining why and what the effects of this LH surge are going to be. Again, we're going to have local secretion of testosterone that's required for female and male germ cell development. That we're going to have inhibins. They are going to decrease FSH production. 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 to consider, the uterus. 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 gonads are 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. 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. We said that the male, throughout his life basically, can make new germ cells. In the female, there is going to be big difference. 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. 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. 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 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. Throughout the month, there are going to be follicles that mature up to a certain point without regard to what's happening with LH and FSH. However, the second part occurs in response to LH and FSH. In this follicle, which is this structure that contains the oocyte, here is the oocyte. It's a very large cell. It's surrounded by granulosa cells. These are similar to the Sertoli cells that are surrounding developing sperm. 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. They they are making testosterone. The granulosa cells, like the Sertoli cells, are the ones that are responding to follicle stimulating hormone. They convert 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. It's follicle stimulating hormone that enables these cells to help the oocyte mature. As we get an increase in LH and FSH, we're going to induce at least a dozen different follicles to start to mature. They 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 at least a dozen follicles are maturing. How do we ovulate only one? 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. 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 its number of LH and FSH receptors so that the follicle will become more sensitive to those hormones. We're having this positive feedback effect. where FSH and LH are produced which causes estrogen to be produced. That estrogen increases the number of LH and FSH receptors so that the cell becomes more sensitive to FSH and LH. These hormones causes more estrogen to be produced. This is one of the few times in the course where we're going to talk about a positive feedback effect. This is estrogen increasing the numbers of receptors that will cause more hormone to be received to cause more estrogen to be made. This one follicle that wins the race is large, producing lots of estrogen, and is very sensitive to LH and FSH. It is now producing enough estrogen that it's going to act on the hypothalamus and pituitary to reduce LH, and particularly FSH production. This then will 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, by decreasing these hormones it is not affected. But the decrease will affect less mature follicles. In this way, we have a chosen follicle that has survived to make the estrogen that eventually lowers LH and FSH but it can survive that drop, because it has so many receptors for these hormones. It is very sensitive to those two hormones. This follicle is then continues to mature even though FSH and LH levels are reduced. The other follicles are now dying, but this follicle continues to mature. It makes a big amount of estrogen fairly quickly. This is estrogen alone. This is now the stimulus that is unique in the female system. This rise in estrogen somehow causes an increase in GnRH production. An increase, in particular, of LH production, luteinizing hormone. That increase in LH is called the LH surge. It's what stimulates ovulation. So once the follicle gets big enough, it is making enough estrogen to cause the LH surge. This causes ovulation. However, we still have those granulosa cells and those theca cells that were making estrogen. That follicle from which the egg just left collapses. It forms what's called the corpus luteum. This is going to be a hormone-producing machine. It produces estrogen like before but also progesterone. So the effect of this LH surge is two-fold. It causes ovulation, that release of the egg, and causes corpus luteum formation. This is basically the luteinizing effects of LH is to form the corpus luteum. That's how it gets its name as the luteinizing hormone. We'll see that the role of the corpus luteum is to produce estrogen and progesterone. How can this happen in the female where now we have this LH surge in response to an increase in estrogen? This is because the female brain develops 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 thes kisspeptin neurons to produce a lot of kisspeptin. That causes the GnRH-producing neurons to produce a lot of GnRH, and that causes the LH surge. 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. 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. It is 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 causes the LH surge. That LH surge is going to lead to one ovulation. Here's the release of the oocyte. from its granulosa cells into the fallopian tube or the oviduct. The second effect of LH is the corpus luteum formation. , That is shown in step five. Now those granulosa cells and theca cells that remain continue to do their job in response to LH. They now not only produce estrogen but also progesterone. That structure will remain, until finally about two weeks later, if there's no pregnancy, then this corpus luteum degeneratea. It will give up and say, okay, we haven't gotten pregnant. It's time to stop and start this thing all over. So it will degenerate, meaning that then, estrogen and progesterone production will dramatically decrease. This loss of progesterone leads to menstruation. The cycle begins again. We'll talk much more about that In the next session. So we've talked about how there is differentiation of germ cells that occurs in the gonad, as well as the formation of sex hormones. That's true for both the ovaries and the testes. We've talked about how LH and FSH have very, very similar roles in the male and the female and how in the female we developed the chosen follicle. But this is an inefficient process in females to produce this chosen follicle. There are 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 estrogen is 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. This leads usually, to just one chosen follicle each cycle. 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 causes the LH surge, which will cause ovulation and corpus luteum formation.