Twenty Nine Flashcards
Describe the journey of sperm from storage in the male to the egg.
Sperm is stored in the caudal epididymis until it is ejaculated. Upon ejaculation, it
immediately forms a gel, but is liquefied about 20-30 minutes afterwards by enzymes
derived from the prostate gland. It is amazing how fast these little guys are…in the
mucus within 90 seconds and in the tubes by about 5 minutes. Even when the mucus is at
its thinnest due to estrogen, the sperm still have to muscle their way through it. The
mucus acts like a filter, perhaps keeping the slower guys out. It also asks like a reservoir.
The sperm hang out in the endocervical crypts for up to 72 hours, and get released in a
time-release fashion. Of the 250 million sperm deposited into the vagina, only a few
hundred ever make it up close to the egg. Most are lost in the vagina.
What is capacitation? What are three steps the sperm go through after that? Explain.
Capacitation is the term to used describe the cellular changes that sperm must go through
while in the reproductive tract (or incubated in an appropriate medium) before they have
the capacity to fertilize. After capacitation, sperm can:
1) Undergo the acrosome reaction
2) Bind to the zona pelucida
3) Acquire hypermotility
This may all have something to do with a modification of their surface charge and the
restriction of receptor mobility. When the sperm is in the vicinity of the egg, there are
changes in the membrane stability that ultimately leads to the acrosome reaction. This
was discussed in a prior lecture, but basically, it allows the release of enzymes to help
penetrate the egg and changes the inner acrosomal membrane so it can fuse to the oocyte
cell membrane.
Describe the journey of the egg from ovulation to the ampulla.
When an egg is ovulated, it is released from the ovary with the surrounding cumulus
oophorus. It only takes about 2-3 minutes for the egg to get to the ampulla of the
fallopian tube. Ovulated eggs/cumulus cells tend to stick to the ovary and the fimbriated
ends of the tube sweep over the surface of the ovary for pick up. Eggs can also be
deposited into the cul-de-sac artificially by transvaginal injection, and somehow the tubes
can find these too. The eggs are transported down the tube by a combination of smooth
muscle contractions and the ciliary-induced flow of secretory fluid in the tube. The
fertilized egg hangs out in the tube for about 80 hours…90% of this in the ampulla. This
is so it can do some developing into a blastocyst capable of implantation, and so that the
endometrium can get itself ready for this blastocyst coming down the tube.
Describe what happens when the egg and sperm meet. What is the acrosome reaction? Cortical reaction? Zona reaction?
Going back to the egg in the ampulla, there is some evidence that the egg may send some
sort of chemotactic signal to the capacitated sperm to help aid it in their journey. Once
the sperm gets through the cumulus oophorus, (which may help in sperm development), it
arrives at the zona pelucida, the mucopolysaccharide shell that remains until
implantation. Sperm penetration of the zona pelucida require that the sperm be
capacitated and hyper motile. When the sperm head receptors and the zona ligands bind
together, they produce an enzyme complex that triggers the acrosome reaction. This
releases enzymes necessary for the sperm and the oocyte membranes to fuse. After the
inner acrosomal membrane of the sperm fuses with the oocyte membrane, the cortical
reaction is triggered. This reaction involves the release of the cortical granule’s contents
(found beneath the oocyte membrane). The release of the contents of these granules
leads to the zona reaction. This is basically a hardening of the zona pelucida and
inactivation of the zona ligands for the prevention of polyspermy. After this, cell division
begins.
Describe what happens as the fertilized egg travels to the endometrium. Describe how the endometrium is prepared.
The pregnancy, as it travels down the fallopian tube, grows into a ball of cells called the
morula and enters the uterine cavity about 3 days after ovulation. While in the uterine
cavity, the morula becomes a blastocyst, which is basically the morula with a hollowed-
out cavity. The blastocyst “hatches” from the zona pelucida after being in the cavity for
1-3 days.
The endometrium has window of receptivity from days 20-24 in a 28-day cycle. This
period of receptivity is heralded by the formation of pinopods, which are progesterone
induced smooth protrusions. The embryo has a tendency to attach to sites with pinopods,
which may be responsible for absorbing fluid, thus forcing the embryo to come into
contact with the endometrium.
What is HCG? What is its function? How can it be used in monitoring pregnancy? How can it be used clinically?
HCG (human chorionic gonadotropin) is the pregnancy hormone detected by home kits
and by blood tests. Its production begins about a week after fertilization. It is
structurally similar to FSH, LH, and TSH (they all have alpha and beta chains). This is
the hormone that rescues the corpus luteum so that progesterone continues to be secreted
to maintain the pregnancy. It is a very useful hormone clinically in following abnormal
pregnancies. For example, HCG doubles about every 48 hours in a normal early
pregnancy. Failure to do so is a red flag that the pregnancy may miscarry or be an
ectopic. If we are suspicious that a pregnancy is abnormal, we recheck the HCG level in
48 hours. If it does not double, we have to be on the lookout for an ectopic, which can be
fatal. We also use HCG injections in infertility treatment. Since it is so similar to the LH
molecule, we can use it in patients to give them an LH surge when we are inducing
ovulation. More on this later.
Describe how the blastocyst adheres to the uterine wall. Briefly describe what happens after that.
As previously stated, the embryo hangs out in the cavity for 1-3 days and hatches from
the zona pelucida (by contraction and expansion of the blastocyst and also some help
from the components of the uterine fluid). The blastocyst usually adheres to the upper
posterior uterine wall about 2-4 days after the morula enters the cavity.
Implantation begins when the trophoblasts bind to endometrial integrins. Integrins are a
family of transmembrane receptors for collagen, fibronectin and laminin. (Fibronectin
and laminin are also expressed by the embryo). These integrins peak at the time of
implantation. The blastocyst also expresses integrins at this time as well. It is not
completely understood what actually happens, but think of these integrins and fibronectin as the glue that causes the embryo to adhere to the endometrium. After implantation,
the trophoblasts invade between the endometrial cells by proteinase degradation of the
extracellular matrix and the placenta is formed in the second week after ovulation. You
know the rest from the previous lecture on the placenta.
What is the function of the corpus luteum? What is the role of progesterone? What is the timeline of progesterone secretion? What happens to estrogen levels duringn pregnancy? What are the 3 parts of the fetoplacental unit?
This all gets started with the corpus luteum. Its primary role is to make
progesterone…think of progesterone as pro-gestation. Progesterone levels rise
throughout pregnancy. Serum estrogen levels also rise. Estriol is the big player in
pregnancy. The steroids are secreted by the ovaries initially, but are replaced by the
placenta at about 8 weeks. If for some reason the mom loses her corpus luteum (i.e. with
rupture, or surgical removal), we need to give the mom supplemental progesterone until
the placenta takes over.
Once the placenta takes over, it becomes pretty bizarre how everything is made. The
placenta; however, can’t do it all alone. The fetus has to help out. Thus comes the term
fetoplacental unit. This has 3 parts: 1) the placenta 2) The fetal adrenal cortex 3) the
fetal liver.
Describe the fetal adrenal cortex. What is its role?
Just a few words about the fetal adrenal cortex. For one, it is BIG. The fetal adrenal
glands are huge when compared to the adult size. There are the 3 outer definitive zones
that you’ve already learned about, the zona glomerulosa, zona fasciculata, and the zona
reticularis. There is also an inner fetal zone. It is this inner fetal zone that makes the
bulk of the fetal adrenal steroids, the majority being DHE(A) sulfate. This DHEA sulfate
goes into the placenta where it is aromatized into estrogen.
Which enzymes does the fetus lack? Which enzymes does the placenta lack? What does this mean? Describe how progesterone is created in the placenta, mother, and fetus. How is it used in the fetus?
The big thing to note is that the placenta LACKS the following enzymes:
16 alpha hydroxylase,
17 alpha hydroxylase,
17/20 lyase (desmolase).
The fetus LACKS:
3 hydroxysteroid dehydrogenase
Aromatase
The placenta can’t move right on the chart from pregnenolone and progestrone to glucocorticoids nor from glucocorticoids to androgens. Therefore, they can’t make estrogen.
The fetus can’t move down on the chart from pregnenolone to progesterone or from DHEA to androgens. Also, even in the presence of androgens, they can’t form estrogen.
Most of the progesterone comes from maternal precursors (progesterone levels remain
high even after fetal demise). Most of the precursors come from maternal cholesterol,
delivered from the bloodstream as LDL cholesterol. The cholesterol passes to the
placenta where it is converted into pregnenolone then back out to the mom as
progesterone. Since the baby lacks the 3 -OH dehydrogenase enzyme, No progesterone
is made from the fetus. Some progesterone is delivered to the baby, since it will be used
for corticosteroid production.
Describe the production of estrone and estradiol in the fetoplacental unit. What is the result? Describe how estrilol is created in the fetoplacental unit.
The pregnenolone sulfate goes through its series of enzymatic steps seen in the first flow
chart, (which I will call diagram #1), until you get to DHA Sulfate, made in the fetus.
Since there is that pesky 3 -OH dehydrogenase enzyme block, the DHA Sulfate goes
back to the placenta, is desulfated, goes through the rest of the steps in diagram #1 and
ultimately, you have androgens converted into estrogens (estrone and estradiol), secreted
back into the maternal circulation. Just follow the diagram above.
The last hormone, estriol, is a bit different. Estriol is the estrogen of pregnancy. In fact
they used to follow this hormone to determine fetal well-being. This diagram shows that
the DHA sulfate goes to the baby’s liver, and there is a new enzyme there (not on any of
the other diagrams). This converts the DHA sulfate to a 16OH DHA sulfate. Basically
it adds another OH group to make it esTRIol….(remember…3 OH groups?). This goes
back into the placenta and through the same pathways in figure #1, gets converted into
estriol.
Describe what happens when the placenta is missing the sulfatase enzyme.
In case you are wondering the functions of all of these steroids, well, join the club. Not a
whole lot is known about how and why things work this way. There is a rare condition
where the placenta is missing the sulfatase enzyme; therefore, it can’t remove the sulfate
groups. This situation demonstrates low maternal estrogen levels and high fetal DHAS
levels. If you think about it, it makes sense. The placenta can’t take the sulfate groups
back off of the precursors, giving rise to high amniotic levels of DHAS and 16OH DHA
sulfate. These moms fail to go into labor and usually require a cesarean section. The
baby’s skin shows ichthyosis, meaning it has scales like a fish, generally on the neck,
trunk and palms and corneal opacities, cryptorchidism and pyloric stenosis.
What is hPL similar to? What produces it? What is its function? What clinical implications does this have? What other function does it have?
This is also called Human Chorionic Somatomammotropin. It is produced by the
syncytiotrophoblasts and it is similar to Growth Hormone (GH) and Prolactin. hPL
increases throughout pregnancy and basically is related to the size of the placenta. The
whole point of this hormone is to make sure that the fetus has enough glucose. What it
does is antagonizes the action of insulin, and is responsible for the diabetic-like state that
the mom experiences during pregnancy. It basically blocks the action of mom’s insulin,
so it does not take the glucose out of the blood and put it into the cells, therefore the
glucose is available for the baby. It also causes mom’s protein and fat to be broken down
and used as an energy source. We always check the mom at about 28 weeks gestation to
make sure that she hasn’t become a full-blown diabetic. This is not good. For one thing,
too much glucose makes the baby fat and fat babies get stuck in the birth canal. This is called shoulder dystocia and is every obstetrician’s nightmare. There are maneuvers that
we can use to hopefully get the baby out, but unfortunately, there are times that the baby
dies or sustains severe injuries from delivery. More about this next year. hPL is also like prolactin in that it stimulates mammary gland development. You also
need estrogens and progestins and prolactin. We will talk more about prolactin when we
talk about lactation.
When does parturition occur? What causes it to occur in sheep? What are some theories as to what initiates it in humans? Describe the role of oxytocin? Prostaglandins? CRH?
This is a fancy word for the delivery or birth process. The funny thing is that as far as
people go…we really don’t have much of a clue how the whole thing gets started.
Human pregnancy lasts about 40 weeks from the first day of the last menstrual period
(LMP). So if you figure that ovulation occurs at about two weeks after the first day of
the LMP, then that gives you about 38 weeks of actual gestation time. In OB we
ALWAYS use the LMP to time things.
So, how does the uterus know when it is time to start contracting and expel the fetus?
Well, in the sheep, it is the fetus that determines when it is time. In a nutshell, when the
sheep’s hypothalamic/pituitary axis is mature, it causes an increase in cortisol secretion.
This cortisol stimulates the production of androgens, which are converted into estrogens.
When there is an increase in the ratio of estrogens to progestins, labor begins.
Not quite so simple for humans though. There is no decline in progesterone levels prior
to delivery. Progesterone administration usually will not stop labor (however there are
studies now looking at different kinds of progestins for preterm labor). The hypothalamic
pituitary axis of the baby probably does have something to do with it. Look at the case of
the anencephalic fetus. These fetuses do not have complete development of the
hypothalamic and pituitary structures and usually deliver past their due dates.
Uterine size may be a factor since multiple births often deliver prematurely.
Oxytocin is a hormone that causes uterine contractions. Cervical stretching (possibly by
the fetal head) results in increased oxytocin secretion. This is one of the medications that
we use to induce labor, but generally after there is already some cervical dilation
Prostaglandins F2 and E2 increase uterine contractility and are used commonly in
obstetrics to soften the cervix and begin the induction of labor. Prostaglandins increase
in amniotic fluid, fetal membranes and the uterine decidua before the onset of labor, but
their exact role is not known. It may be through this local mechanism (that is not
reflected in the maternal serum) that parturition in humans may be initiated.
One final word is that CRH (corticotrophin releasing hormone) may be involved with the
timing of delivery in humans. Here is how this works. CRH is synthesized in the placenta as well as the fetal brain.
CRH leads to the increase of fetal pituitary ACTH secretion, which causes secretion of
cortisol by the fetal adrenal gland. This cortisol leads to fetal lung maturation. This CRH
released from the placenta leads to ACTH from the fetal pituitary gland. This causes an
increase in fetal DHEA sulfate. This is ultimately converted into estrogen, which may
lead to an increase in oxytocin receptors, prostaglandin production and ultimately labor.
I realize that this is vague, but it is a theory.
What is milk production under the influence of during pregnancy? Explain. What happens after delivery? What role does oxytocin play? What causes menstrual cycles to cease during pregnancy? During breastfeeding? How fool proof is this? Explain.
Late in pregnancy, the alveolar cells in the breast contain vacuoles filled with milk. This
is under the influence of estrogen, progesterone, glucocorticoids, prolactin and hPL.
Prolactin levels rise during pregnancy, but due to the high levels of estrogen and
progesterone, milk is not secreted into the duct system. Once the baby and the placenta
are out, the negative influence of estrogen and progesterone are gone as well and
lactation can begin. Remember that prolactin is a unique hormone, mostly under
negative feedback by dopamine.
Prolactin is responsible for the synthesis and secretion of milk, but it is oxytocin that is
responsible for milk to be ejected out of the duct system. Oxytocin causes the contraction
of the myoepithelial cells around the alveoli, thus leading to milk letdown. Prolactin
levels are high after delivery, but eventually return to normal levels and surge whenever
the mom nurses. External stimuli are also responsible for milk letdown, for instance a
breast-feeding mom experiencing breast leakage at the sound of a baby crying due to
release of oxytocin.
The menstrual cycles cease during pregnancy due the negative feedback of the high
levels of estrogen and progesterone on FSH and LH (which makes sense…why would
you need to ovulate if you are already pregnant?). During lactation, prolactin does the
same thing, but eventually, when prolactin levels fall back to normal, FSH and LH
cyclicity returns. That is why some women can become pregnant even while
breastfeeding.
