Hello. We're going to finish the female reproductive system. We're almost there. We now understand how the cycle of the ovary occurs, but to understand the full menstrual cycle we've got to understand what happens with the uterus. So that's what we're going to talk about. First, we're going to just talk about the ovarian cycle a little bit more. Where we will consider the different phases of the follicle in the ovary. As well as the different amounts of estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone that occur throughout the cycle. The menstrual cycle is going to start with menstruation, the first day of menstruation. Because that's the only day when it's obvious where you are in the cycle. That's day one of the cycle. At the beginning of the menstrual cycle, there is just a small increase in FSH and luteinizing hormone. That is going to cause the follicular phase of the cycle, which is when the follicle starts to mature or continue to mature. Remember the first part is not dependent on GnRH or LH or FSH, it's the second part of maturation. That's what's going to start because we have a little bit of an increase in LH and FSH. We are going to have our follicles maturing, making more and more estrogen. We're going to have our chosen follicle make a lot of estrogen enough to now have a small decrease in LH and FSH production. This decrease will kill the other maturing follicles. Then, finally, we have the maturing follicle large enough that it produces this large, rapid increase in estrogen. This rise acts on that second group of kisspeptin neuron to cause the LH surge. That's what's shown in green right here. This LH surge, triggers ovulation, release of the egg, and causes corpus luteum formation. The granulosa cells and theca cells remain. They continue to make estrogen, as shown right here, but also increase dramatically the amount of progesterone made. That will continue for a certain amount of time, [COUGH] until eventually, the corpus luteum degenerates. When it does that, it stops producing its hormones. Estrogen and progesterone will fall dramatically. If they fall, or when they fall, decrease in levels, then that allows a small increase in FSH and LH levels. Which is what we said happened at the beginning of the cycle to start another round of follicles to mature. That's what happens at the end, and that's why, at the beginning of the cycle we have the small increase in FSH and LH, which cause a whole other cohort of follicles to start to mature. Because the corpus luteum just degenerated, then estrogen and progesterone levels fall. GnRH increases. Now let's add in the uterus. We're looking at the same figure, but have added the uterus to the bottom of the figure. Where we said there is this drop in estrogen and progesterone because the corpus luteum says, okay, we didn't get pregnant. We'll have to try again next time. We'll degenerate. As a result of that drop in estrogen and progesterone, remember the ovary in controlling the uterus. It's that drop in estrogen and progesterone that is the signal, okay, we didn't get pregnant. Uterus, you need to start with a clean slate, almost literally. Menstruation happens when the lining of the uterus sloughs off. That's what's happening for roughly the first week of the cycle if there is no prenancy. The corpus luteum degenerates, so estrogen and progesterone fall. That's the signal to the uterus it's time for menstruation. The lining of the uterus, which is what's shown in this bottom figure, sloughs off during menstruation. Then, during the follicular phase, or later during the follicular phase, we've got this increase in estrogen coming from the chosen follicle. Estrogen, by itself, causes the proliferative (growth) phase of the uterus. Where menstruation occurred, we need to build back up the lining of the uterus. The estrogen coming from the chosen follicle is what causes that proliferative phase of the uterus. It can build itself back up. Then, in the second half, in the luteal phase when we've got the corpus luteum active, we've got estrogen and progesterone. That causes the secretory phase of the uterus. The glands are still getting taller (growing), as you can see in the diagram. But they are also starting to secrete substances. Basically, the lining of the uterus is getting ready to possibly receive a developing embryo. The estrogen, and very specifically, the progesterone are needed to put the uterus into the secretory phase to begin the final stages of preparing for the implantation of an embryo. That will continue until if there is no pregnancy, there is degeneration of the corpus luteum, sloughing off and menstruation occur again. So you can see how the hypothalamus and pituitary are controlling the ovary., The ovary controls the uterus. It determines what phase it's in. What happens if we do have a pregnancy? Then the embryo is going to start to implant in the uterus. In the region that was prepared by the secretion of estrogen and progesterone. The implanted embryo will make a hormone called human chorionic gonadotropin, or hCG. This hormone is very similar to LH. It binds LH receptors. Remember that LH formed the corpus luteum. So hCG will bind those LH receptors and maintain the corpus luteum. The corpus luteum will continue to produce estrogen and progesterone. If estrogen and progesterone remain elevated then the uterus remains in the secretory state. We will have menstruation. GnRH levels remain low as well. So we will not start a new cycle as long as hCG is produced. hCG maintains the corpus luteum, maintains estrogen and progesterone production so we don't have menstruation and GnRH remains low. hCG is what will spill out into the urine. THis is what is measured in an at home urine pregnancy test. It can also obviously be measured in the blood. We'll see in this slide, how hCG levels rise dramatically at the beginning stages of pregnancy. These are hormone levels at different months of pregnancy. You can see that is zero on the first day of menstruation. So about a month later when finally the embryo is implanting, now there is lots of hCG made. You can see how dramatically it increases. Then it also dramatically decreases at about the end of the first trimester at three months pregnancy. As a result of hCG no longer being produced, there corpus luteum will now start to degenerate. So instead of degenerating at the end of the menstrual cycle, is now degenerates at the end of the first trimester. Estrogen and progesterone will no longer be coming from the corpus luteum. That's okay. You can see estrogen and progesterone levels continue to rise throughout pregnancy, because now out here, it's starting to be made by the placenta. So, at the end of that first trimester, there's a shift from estrogen and progesterone being made by the corpus luteum to being made by the placenta. This continues until delivery. There is a rapid decrease in both hormones as the delivery of the baby. Let's go back to thinking about some of our estrogen and progesterone target tissues like the uterus, and the characteristics of estrogen and progesterone actions. Remember, we said that estrogen alone makes the uterus grow, be in the proliferative phase, where builds back up. That's going to be in the first half of the menstrual cycle. When this happens, we have estrogen by itself. It acts to increase its own receptor. So again, it's gonna be this positive feedback action. Where you have estrogen, it will cause an increase in the number of estrogen receptors. This means the tissue is more sensitive to estrogen. Estrogen is also going to increase the number of progesterone receptors. We call this process priming. Priming because at this time we don't have progesterone around, but soon, once the corpus luteum forms, we will. So, estrogen gets the tissue ready so that it will be nice and sensitive to progesterone once progesterone is made. In this way, estrogen acts to cause proliferation rapidly, by making the tissue more and more sensitive to it. Then it also prepares the tissue for progesterone, by causing expression of progesterone receptors. Now, you need to stop this somehow. Because you don't want to keep proliferating, growing. So progesterone is going to be important, because it acts to reduce the number of estrogen receptors. This stops growth. Stops that positive feedback of estrogen to increase the number of estrogen receptors. Progesterone's gonna stop that by decreasing the number of estrogen receptors. This shows why giving estrogen only can possibly cause cancer of the uterus, of the lining of the uterus, if it's without opposition from progesterone. If you have estrogen by itself, that can be a dangerous thing in terms of cancer of certain tissues like the uterus, which are estrogen responsive. You need to have some progesterone around to decrease the number of estrogen receptors. Let's move now to talking about oral contraceptives, where we are going to reduce the amount of GnRH in order to prevent pregnancy. The first birth control pills were produced in the early 1960s. The first one was called Enovid. It was composed mostly of progesterone with a little bit of estrogen. The estrogen originally was there as a contaminant. Once they realized that and it was removed they realized that to have a little bit of estrogen there was good, in terms of some of the side effects it prevented. So the pills were mostly progesterone with a little estrogen. The progesterone will reduce the amount of GnRH produced and will prevent the LH surge. In the 1980s, there was a big change with birth control pills because they started to be made with synthetic hormones which allowed them to be much smaller doses of hormones because they had a much longer half-life. So these pills in the 80s had 10 to 20 fold lower levels of hormones than the earlier pills, and caused fewer side effects as a result. Birth control pills, as I said are going to act to keep GnRH low. They act to prevent ovulation by preventing the LH surge, but they also have other effects that are very important as well as preventing pregnancy. One is to alter the mucus in the cervix which is the first part of the uterus. This makes the mucus sticky so that sperm can't enter the uterus. It is another very important effect of the birth control pills. Then there are also other changes in the uterus and oviduct that make pregnancy less likely as well. So it's just an important illustration of, basically, the negative feedback nature of this system. Just like we've seen with so many of these hormone regulation or regulatory systems in the body. Where if you add extra hormone you're gonna depress the axis. We've talked about now, in the follicular phase of the ovary, the uterus is in the proliferative phase because we're producing estrogen. Then in the luteal phase of the ovaryy when we have the corpus luteum there is estrogen and progesterone, now the uterus is in the secretory phase. It's ready for implantation of an embryo. If we do have implantation, then we're gonna have hCG from the embryo, which acts very similarly to LH, to maintain the corpus luteum. That's will last for the first three months. Then after the first trimester, the corpus luteum degenerates and cause hCG levels to fall. That's okay because the placenta takes over the production of estrogen and progesterone. Then we finished up talking about how oral contraceptives act to reduce LH and FSH release by suppressing the H-P axis.