5. Fertilization process (how sperm reaches egg) Somewhere along the line, if sperm are deposited in the vagina, they swim up through the cervical canal, and the cervical mucous changes its character with this monthely cycle. So that, its generally a firm, fairly viscous, hard to get through barrier separating the uterus lining from the vagina. But at the time of ovulation or there abouts, perhaps because of this big peak of estradiol and progesterone going up, the characteristics of this cervical mucous changes and it becomes easier for the sperm to swim through it. So the sperm swim into the uterus and meanwhile presumably, coming down one of the fallopian tubes, there is an egg. So the sperm are faced with their first choice. There are chemicals that tend to draw them into the cervical mucous so they tend to swim through it into the uterine lining. But then they are faced with two fallopian tubes. Which one do they head for? Well as everyone knows, men wont ask for directions. So about half of them go one way, half of them go the other. And they swim up the fallopian tube. Now somewhere, about 2-3 days after ovulation, the eggs coming down, the sperm are swimming up. And theres now a question of, does one of those sperm head for the egg? Out of a billion sperm that are swimming there. Or is it purely random? In some animals - its still an open question by the way in some animals, eggs release an attractant that the sperm, that make the sperm swim towards it. And in humans there are few candidate chemicals that have been found as sperm attractants for human sperm. But its never been demonstrated that the egg in the fallopian tube ever secretes one of them. So its a possibility, has not been ruled out, but not established either. It may just be that thats why it takes about a billion sperm to fertilize just one egg. Because if you send enough, one of them will bump into it, purely blindly. And of course, the other half of the sperm that went up the wrong tube are totally wasted anyway.
Transcribed by Jazmin Lui May 10 2014
6. Fertilization (mechanism of the sperm fertilizing the egg) So assuming that a sperm eventually meets that egg, well first of all lets take a look at the sperm. And this is human sperm, it may be different from other species. But basically youve got your sperm, youve got your, its almost all nucleus. And then youve got a sort of neck here, and heres where all the mitochondria are. And they provide the energy, the ATP, for the tail to sort of wiggle around and send the fellow swimming. Now when the head of the sperm penetrates the membrane of the egg so heres egg, alright the tail gets left out including the neck. This is where humans may or may not differ from other species. And the only reason Im bringing this up is forensically and in other forms of research, youll notice that Daddys mitochondria dont get into the egg. Mitochondria have their own DNA which is referred to as mitochondrial DNA, small m small t DNA. And you have the same, your mitochondria have the same mitochondrial DNA as your mother. As your mothers mitochondria. And she has the same as her mothers mitochondria. So all mitochondria that end up in the eventual offspring of such a fertilization are maternal. The sperm DNA, er mitochondria, get dumped in the garbage. Because the head of the sperm is separated at the neck, and the mitochondria stay on the outside. So in terms tracking ancestry, we need, we may not be able to track paternally all the way to Adam, but we can track all the way back to Eve with mitochondrial DNA. Thats pushing it a little isnt it? There are gradual changes over the millennia and mitochondria have developed and things go on. Alright.
7. Hormonal levels after no fertilization of an ovulated egg Now weve got here, weve got a fertilized egg, maybe in the fallopian tube and its heading down to the uterus. The uterus meanwhile is developing its very thick and cushy endometrial lining. And this is creating a little nest for the embryo as it swims. It doesnt swim. As its carried, like driftwood or whatever, in the currents. Now there are 2 possibilites here. One is if fertilization did not take place. If fertilization did not take place then LH and Transcribed by Jazmin Lui May 10 2014
FSH decline and continue to decline, to the point where they are no longer stimulating the production of estradiole and progesterone from the corpus luteum. In fact LH is needed for corpus luteum maintenance. So if after about 11 or 12 days following ovulation when the corpus luteum formed, the corpus luteum begins to degenerate. And as the corpus luteum degenerates it stops producing estradiol and progesterone. And what happens is the estradiol and progesterone levels begin to fall, in fact even further than that, cause youll eventually get back up here, and the progesterone levels will fall even more. Now, progesterone is the hormone that provides for the maintenance of the endometrial lining and its vasculature. So if there is no fertilization, LH begins to fall, corpus luteum begins to degenerate, progesterone levels continue to fall. Without the progesterone to maintain it, the endometrial lining begins to break down. And eventually, day 28, which is day 1, or if day 29 was 1 (otherwise wed be in a 27 day cycle), is the loss of the uterine lining. Which is mostly myometrial tissue, and theres some blood loss of course. Now, thats as long as fertilization does not take place. And now youre back here, with low LH and FSH. Sorry, butyour levels of LH and FSHit doesnt matter theyre both low. As long as the levels of LH and FSH levels are low, your estradiol levels get low, theres no longer a corpus luteum capable of producing progesterone or estradiol, so the main estradiol, that estradiol is gone, and the only source of progesterone at this point is gone. So without the progesterone you lose the endometrial lining, and everything is reset to day 1 and we start this cycle all over again. OK.
8. Changes in hormones during puberty Now again let me just sort of back track to the beginning. All of this starts at the age defined as puberty, which is in women is defined as the age of menarche, which is the first menstrual flow. Which is a sign, that says basically, great landmark, you couldve gotten pregnant 2 weeks ago. And this is typically around age 11 nowadays, same thing for males as of a century ago it was older, back in Shakespeares time it was a lot younger. But again, Transcribed by Jazmin Lui May 10 2014
the gonadotropin releasing hormones are before puberty, being released at a steady rate and then this oscillation occurs, same as in the males. And the gonadotropes are more sensitive to the slowly oscillating levels of the gonadotropin releasing hormones so they start producing much higher levels of LH and FSH, and everything sort of follows from there. Okay, hm, I seem to be actually going faster than I expected. Oh well. We can survive. It wont be a major tragedy if I end early. This is the beginning of the fertile age range for women. Unlike men, theres an end to the fertile age range for women. And well get to that later.
9. Development of the embryo and implantation
Suppose however, that one of those sperms got lucky. And find the egg and fertilize it. Well, this now diploid egg which we can actually start referring to as an embryo. As it floats down the fallopian tube it begins to multiply. And then it goes mitosis and mitosis and mitosis and mitosis. And it goes from 1 cell to 2 cells to 4 cells to 8 cells and so on and so forth. Somewhere around the 32 cell level the cells, which up to now are identical, after all, theres your gospel, mitosis makes 2 identical cells. Somehow, at about the 32 cell stage, the cells at one end of this embryo begin to differentiate from the others. Transcribed by Jazmin Lui May 10 2014
Whether it has to do with some gradient of nutrient of the fluid its floating in, its not clear what. Part of the embryo, some of the cells in the embryo begin to form a specialized organ. They form trophoblast cells. And what a trophoblast cell is, is its secreting, it secretes a hormone, these are the cells that eventually become placenta. As we go into pregnancy. But these trophoblast cells are endocrine cells. And they secrete hCG. Which I mentioned a couple days in the context of the child born with undescended testes, the male child born with undescended testes. Thats whats injected into the child on the first attempt to bring about testicular descent into the scrotal sac. And hCG, human chorionic gonadotropin, its a gonadotropin and in fact it mimics LH. And it does what LH normally does. And what does LH normally do? It maintains the corpus luteum. So whats happening here is, as LH falls, the corpus luteum, if theres no fertilization, degenerates. And you lose your estradiol and progesterone production, and thats that. But now, this embryo, the trophoblast cells in the embryo, start producing hCG. What effect does that hCG, as the embryo is floating down the fallopian tube, have on the corpus luteum at that point? The answer is none. Why not? Well where is it being secreted? As part of the fluid flow towards the uterus. Wheres the corpus luteum? Its up on the ovary. How is that hCG going to get up there? Theres no way. This is essentially totally useless hCG. But nevertheless its secreted at this point. Once this embryo has reached the uterine lining, which is highly vascularised and thicky and cushiony, it implants itself in the uterine lining where the trophoblast cells eventually start producing a placenta. Now those trophoblast cells, while part of the placenta, are producing hCG. hCG now gets into the maternal circulation and can reach the ovary. So its not until a few days afterwards theres a, so if youre basing a pregnancy test, for example, on a urine test. Urine comes from the kidneys. The filtrate has to come from the bloodstream. There has to be hCG in the bloodstream to test for it in urine, right? So its not going to be until you actually have an implanted fetus that youre going to see a positive pregnancy test. Now those who rationalize plan B, the medicine, the drug, saying no its not an abortion, Transcribed by Jazmin Lui May 10 2014
well. Well you dont know to take until you have a positive pregnancy test. If you take it before the positive pregnancy test, on the odd chance, because youve had unprotected intercourse, then you shouldnt get into trouble with the priests. But as the old saying goes, they dont play the game they shouldnt write the rules (laughter). Ok. Once the hCG is in circulation it means this embryo has now been implanted in the uterine lining, because otherwise the hCG would never get into the general circulation and reach the corpus luteum or reach the kidneys. Oh, plan B, by the way, its an antagonist at the progesterone receptors. So for all intents and purposes when you take plan B its as if the progesterone isnt there. And it causes the uterine lining to slough off. Which is about as safe as you can get. Now, ok.
10. Hormonal levels after implantation So what happens now is this. If you have hCG, that is, you have this embryo (which we now call a fetus once its implanted) in the uterine lining. And even though LH is down, the hCG mimics LH, so the hCG is low, but the corpus luteum is being maintained. And it continues to produce estradiol and progesterone. So your estradiol stays up, your progesterone stays up, and the uterine lining is stabilized. And theres a nice environment for junior to grow in. And the hCG being produced by the trophoblast cells which are now part of the placenta, will keep the corpus luteum going for about 3 months. Which is not a whole pregnancy but other things happen in the interim. Ok.
11. Role of the placenta So now we have an established pregnancy, high estradiol, high progesterone, the uterine lining is maintained. A placenta forms which is basically a sort of dual layer of maternal tissue and fetal tissue that interweave with each other, that interdigitate, over the whole surface area. And the actual clinical problems that may follow, Dr. Curry will be discussing tomorrow in the CCP. So, where are we going from here? Well, youve got this placenta developing. The placenta itself differentiates into an endocrine organ among other things. Transcribed by Jazmin Lui May 10 2014
I mean its main purpose, its main function (I shouldnt say purpose), its main function is to allow communication between the capillary bed on the maternal tissue and the capillary bed on the fetal tissue, and so oxygen gets move from maternal blood stream to fetal blood stream. Carbon dioxide is removed from the fetal blood stream to moms blood stream so that mom can breathe it out, nutrients are transferred from mother to fetus, and the little fella grows from this big to this big. At which point he decides he wants out. Or she. Now whats going on here? After 3 months, or so, the corpus luteum is going to atrophy away anyway, or involutes, it becomes a corpus albacans, thats just means white body. You can use autopsy to tell how many pregnancies a woman has had by the number of corpora albacans on her ovaries, because each one indicates a pregnancy that lasted at least 3 months. Doesnt mean delivery necessarily. Because once the corpus luteum has been maintained by hCG for the first 3 months and then declines, it forms a corpus albacans, and thats a little notch on the bedpost saying theres been a pregnancy for at least 3 months. Right. Thats the scoreboard. Whether that pregnancy ever completed is not indicated.
Transcribed by Jazmin Lui May 10 2014
12. The role of hormones in the development of the maternal breasts
What we have now the placenta acting, beginning to act as an endocrine organ. And the placenta produces estradiol, it produces progesterone, and it also produces a hormone called hCS, the small h is human, choronic, this is somatomammotropin. That by the way, only appears several months into pregnancy. And what does it do? Well the somatropin part indicates its behaving as a sort of growth hormone for the fetus. You kind of expect that there would have to be one. The mammotropin, it promotes the maturation and development of a womans breasts. Cause after all, once the little fella is out he has to be fed. From the hypothalamic pituitary axis, youre going to get prolactin formation. Between them, between the hCS and the prolactin, and also progesterone and estradiol contribute too, all 4 hormones lead to the enlargement, development, and maturation of the maternal breasts. They are capable of producing milk. The point here, as a side point, is this development and maturation of the breasts only has to happen once. Dairy Transcribed by Jazmin Lui May 10 2014
farmers knows this. The cow only has to go through one pregnancy and then shes a source of milk forever, well for the rest of her life. This development of the milk secreting process structures in the breast only has to happen once, with the first pregnancy, and then it remains. One of the side effects is a darker pigmentation of the areola, whether it helps the baby find it I dont know, but it is, and that remains. Ok.
13. Changes just preceding birth in the baby So now weve got 8 and half months more of this going on, and eventually a number of things start to happen as the pregnancy nears term. 1) The lungs in the fetus begin to develop surfactant, did Dr. Pavlov discuss that? Yeah, ok. You know what it does, it enables the lungs to expand uniformly and not shift all the air pressure into one large alveolus, basically. And the surfactant doesnt exist before 7.5 months of pregnancy. But then the baby starts to produce it. There are ways if you anticipate clinically that a baby has to be delivered early and you want it to live, to induce surfactant production earlier, but it kind of messes up a lot of things. Its generally to be avoided if it can be avoided. So at the end of, as you near the end of the pregnancy, something else begins to happen. And that is some sort of signal is released from the fetus into maternal circulation, basically saying, Im getting ready! You better be getting ready, Im out of here. And its not known what exactly that signal is.
13. Hormonal changes just preceding birth in the mother But one thing that does happen is, towards the end of the pregnancy, theres a beginning of a drop of progesterone in the mother. Now what you also have to know is that the hypothalamus, you know the neurohypophysis, the posterior pituitary the ones going into herrings bodies and all that. It wasnt that long ago you should all know it. The hypothalamus is releasing oxytocin. Now oxyctocin has a number of functions which well be getting to. But one of them is to depolarize and cause contractions in the uterine smooth muscle. Transcribed by Jazmin Lui May 10 2014
So as you near the end of pregnancy the hypothalamus is getting this signal as well and releasing oxytocin which is trying to cause the uterus to contract and expel this little fellow. Progesterone meanwhile, hyperpolarizes the uterine smooth muscle and keeps it relaxed. So these two hormones, the progesterone and oxytocin, are in a sense battling each other. The progesterone, well look at its name, its pro gestation. So it wants to preserve the pregnancy. Thats its main role, it preserves the uterine lining and stabilizes the uterus. The oxytocin stimulates certain smooth muscle in the body to contract. And in this particular case, the oxytocin will promote contraction of the uterus which will eventually expel the uterus. So what happens? Somewhere this signal from the fetus comes out and says drop the progesterone levels. At which the uterus gets more sensitive to oxytocin and contracts. Now this is not an all of a sudden, turn on the switch and out pops the baby. You should be so lucky. Youre talking days in some cases. If for some reason the physicians present think it advisable to prolong the pregnancy, and delay delivery, they can infuse additional progesterone. If on the other hand they want to speed this whole process up, they can infuse oxytocin. Which will speed up the uterine contractions and get it all over with. And then suddenly, at some point, 40 or so weeks after all that started, you end up delivering another human being, which is nice.
14. Placenta after birth Now if, once this human being is delivered there are a number of things going on. Following this person coming out, generally the placenta has to come out as well. The placenta is essentially, remember, this interdigitated mess of brush border, two brush borders sticking together, its like Velcro. And youre ripping it off and youre taking some endometrium of the maternal tissue with it. Theres going to be, among other things, bleeding. Other primates, not humans generally, perhaps in some cultures, eat the placenta. The mother does. It restores some of the iron thats being lost in the bleeding, nutritious tissue or whatever. Gorillas do, chimpanzees do. A lot Transcribed by Jazmin Lui May 10 2014
of other species do, humans tend not to. Humans are the only animals that have this yuck factor. But now youve got this uterine lining bleeding. Well get back to that.
15. Milk letdown reflex and role of oxytocin The baby meanwhile, is generally immediately put to the mothers breast to feed. What does that do? Well first of all, babies, especially if theyre vaginal deliveries, have their noses squished in as they pass through a smaller passage. Caesarian section deliveries, not so much. But for the most part, this and other reasons, in the early days the baby is an obligate mouth breather. Theres mucous in the nose and the nasopharynx which they generally suction out but they also, theres also this pressing of the nose in vaginal delivery. And so this fellow cant really suck. Take your coke, put a straw in it, and try to drink. It doesnt work very efficiently. Because if you have to breathe through your mouth you cant do continuous sucking. So what happens is early on at least, theres a reflex pathway, called the milk letdown reflex. The duct system that Dr. Lopez described are the myoepithelium. Its epithelium but theres some characteristics of smooth muscle. Youve got your muscle, youve got your actin-myosin, youve got your contractile ability. And the milk ducts contract in response to oxytocin. And where does oxytocin come from? The hypothalamus by way of the posterior pituitary. So what happens is, you stimulate the nipples, the baby does, hes licking there. And that signals the hypothalamus to release oxytocin. The oxytocin causes the milk duct to contract, and the milk is ejected onto the surface of the nipple and can be licked up. So he doesnt actually have to suck. But what else does oxytocin do? Well it causes the uterus to contract. Remember you have this new delivery, youve ripped out the uterine lining. Its bleeding, youre all certified in first aid or you should be soon. What do you do if theres a large bleeding surface area? Pressure dressing. You apply pressure to it to promote coagulation to stop the bleeding, so heres what you want to do. You want to produce oxytocin to cause the uterus to contract which will put pressure on Transcribed by Jazmin Lui May 10 2014
the bleeding surfaces and slow down the bleeding and promote coagulation. So thats why breast feeding is good for the mother as well. Because it will reduce uterine bleeding post-partum.
16. Oxytocin inhibits mothers hormonal cycle (no ovulation) Theres another effect of breast feeding. Because while, the hypothalamus gets this message to secrete oxytocin, its also sending a message to turn off its release of prolactin inhibiting hormone, and assuming theres a prolactin releasing hormone, it probably promotes release of that, theres question about that. But, in any case prolactin is released from the pituitary lactotropes in response to stimulation of the breasts. So as long as youre breast feeding, well you not me, but as long as the mother is breast feeding theres going to be increased release of prolactin. And the prolactin will keep the milk production apparatus going so that basically as long as the baby is drinking from the breast, the breast will keep producing milk, to provide for the baby. Now theres an interesting side effect of this, which has long been known and passed down like mitochondrial chromosomes, mitochondrial DNA rather, from mother to daughter over the centuries. Its known at least as far back as the rennaisance. And that is, when the hypothalamus gets signal that you are breastfeeding, and it releases prolactin, it also decreases the release of gonadotropin releasing hormone, which decreases the production of LH and FSH. Which can essentially slow down or stop the entire hormonal cycle. So that the mother who keeps breastfeeding may remain amenorrhoeac for a long period of time. Not cycling. So breast feeding leads to a reduction in fertility. This was known in the renaissance as indicated by diaries of wealthy women. And you have to consider at this time, the most dangerous thing a women could do, to risk her life, was to get pregnant. Generally they didnt have a choice in the matter, because the husband was considered to have the right to rape his wife. But the women didnt want to, having gone through the lovely experience once, didnt want to have to go through it again. So the practice became, back then, to continue to breastfeed the children up to age Transcribed by Jazmin Lui May 10 2014
6 or 8 or 10 years, not months as a way of reducing the chance of getting pregnant again. Because while the hypothalamus is releasing prolactin releasing hormone or not releasing prolactin inhibiting hormone its also releasing a lot less gnRH and you end up with reduced fertility. So, thats a useful thing to know. Is there something else I wanted to cover? Or are we leaving earlynursing, nipples, milk ejection, okay. I think this is going to be a very short lecture actually. So basically this is what is going on in the whole process. You dont have to, the actual day to day clinical ramifications of the possibility of pregnancy inducing a form of type II diabetes. You heard it from Dr. Hammer last week and youll probably hear about it from Dr. Curry tomorrow. Youve got pregnancy and gingivitis to worry about, youve got the assorted other things that can happen.
17. Fetal and maternal hemoglobin By the way, you do remember blood chemistry of pregnancy. The fetus has hemoglobin F which has a higher oxygen affinity than the hemoglobin A or B that the mother has. So if you have a given oxygen partial pressure and you have some hemoglobin A blood and adjacent capillary hemoglobin F blood, the oxygen will move to the fetus. So the developing fetus is drawing oxygen from the mother through the placenta. Children are generally born still having hemoglobin F and over a month or so it gradually converts to hemoglobin A. Ok, yeah were a half hour early. Howd we do that. Any questions?