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Transcribed by Jazmin Lui May 10 2014


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?