Repro Embryo Flashcards
inhibin A in down syndrome?
increased in blood of mom and fetus!
protein secreted by ovary to inhibit FSH
inhibin A
protein secreted by the ovary and is designed to inhibit the production of FSH by the pituitary gland
inhibin A ins increased in the blood of mothers and fetuses with Down syndrome
embryonic sequence
pattern of multiple anomalies derived from a single known or presumed prior anymaly or mechanical factor, leading to scondary effects in develipmetally unrelated structures i.e. Potter (anmitioc fluid loss
development of the prostate
outpocketing of the prostate gland (Fig B) from the urogenital sinus and this is driven by the presence of DHT.
embryologic origin of the vagina?
And this shows us how two paramesonephric ducts meet, you get the septum degenerating and the induction from that urogenital sinus causing the sinovaginal bulbs which will also canalize, showing us that the vaginal canal has a dual embryological origin. The upper part = mesoderm from the paramesonephric duct, while the lower part remains endoderm from the urogenital sinus.
embryonic disruption
morphologic defect of an organ or larger region of the body resulting from an extrinsic breakdown of, or interference with, an originally normal developmental process
i.e. ambiotic bands - blood supply cut off after a structure forms - prevents growth and often leads to loss of structures
retinoic acid
for acne and psoriasis in 1980s
cause facial abnormalities
many didn’t know they were preg!
parietal vs visceral mesoderm
And here we can see through the 21 day embryo, you can see how the mesoderm that comes to overlie the ectoderm is called parietal, and that surrounding the endoderm is called visceral. And sitting on the posterior wall is this large area of intermediate mesoderm.
paramesonephric tubercle
female
Here you can see the degeneration of the mesonephric duct in blue (Fig A) and this burnt orange is the development of the paramesonephric duct. The two paramesonephric ducts (one on either side) come down, move to the mid-line and meet each other. And a couple of things happen when they meet each other. When you put two straws together, you have a wall between them. So you have to first cause the degeneration of that septal wall to make room for the uterine cavity (Fig B).
In addition, when the two paramesonephric ducts come together, they touch on the urogenital sinus and cause the induction of what’s called his paramesonephric tubercle (Fig A). Because of this induction, the urogenital sinus will grow posteriorly and help give rise to part of the vaginal canal
what are the male derivatives from the mesonephric kidney?
So in the end, in blue (Fig B) are all the derivatives left from the development of the mesonephric kidney. And all of this develops under the influence of testosterone. So efferent ductules, epididymis, vas deferens, seminal vesicle, common ejaculatory duct – all derived from intermediate mesoderm because of the presence of testosterone.
what enzyme converts testosterone into DHT?
There’s an enzyme called 5-alpha-reductase that converts testosterone into dihydrotestosterone. And the presence of dihydrotestosterone will drive development of two things: prostate gland, external genitalia.
malformation syndromes
series of conenital malformations in different structures that results from an underlying defect in a single molec gene or process
VACTERL
CHARGE
known pways or TF used in many organs
embryonic tissue of the urogenital sinus?
endoderm
Since the lower half/two-thirds of the vagina comes from the urogenital sinus, it’s going to be derived from endoderm.
paramesonephric duct
develops in the female after the indifferent stage
The primordial germ cells have finished their journey, they’re populating the genital ridge. You have the presence of the mesonephric and the paramesonephric duct. Now you have no SRY region because no Y chromosome. Without the SRY region, you’re not going to have Leydig cells producing testosterone, so what is going to happen to the mesonephric duct (in blue)? Without testosterone, it will degenerate. Why will the Paramesonephric duct (in orange) develop instead? Because MIF is missing. There’s no sertoli cells to secrete MIF so now you have the reverse. The mesonephric duct degenerates. It is the paramesonephric duct that will now begin to develop.
what embryonic layer is paramesonephric duct from?
mesoderm
turner’s syndrome
45XO (missing a chromosome)
in Turner’s Syndrome, the individual doesn’t develop any secondary sex characteristics because the follicles never reach a level of development where they can produce estrogen.
webbed neck is characteristic
Check hormone levels (gonadotropins, estrogen, testosterone) à FSH and LH normal, testosterone normal for female, estrogen levels really low.
Check her genotypeà karyotype is 45 XO (missing a chromosome).
Ultrasound pelvis à uterus, fallopian tubes, ovary, internal duct system looks good on ultrasound
Ovarian biopsy à immature and degenerating follicles – never reach the maturity needed to produce estrogen
Inspect neck à the sternocleidomastoid splays out laterally instead of coming down at a sharp angle = appears as a “webbed neck” = indicative of a genetic anomaly called Turner’s Syndrome
fetal alcohol syndrome
distincitve facial features - flat midface, low nasal bridge, short upturned nose, thin upper lip
microcepharly
mental impairment, delayed evelioment, learning problems, abormal behavior (hyperactivity, short attention span, no impulse control)
even moderate drinking can cause a problem
may manifest later!!
germ cell migration
So in about a 3-week-old embryo, the primordial germ cells actually lie in the yolk sac (mouse Fig A). And during the development, the primordial germ cells will journey up the dorsal mesentery to populate the genital ridge. So what happens is these germ cells schlep up the dorsal mesentery (schlep, it’s an embryological term. It means to move.) and they’re going to populate the genital ridge with a presumptive gonadal form.
Now, arriving at the genital ridge to begin the formation of the gonads is critical. The timing is critical. You need to population this in a certain amount of time, somewhere between 4-6 weeks. If the primordial germ cells do not reach the ridge at that time, then the gonad will not develop. So timing is critical. And if the primordial germ cells do not arrive on time, and if the gonad doesn’t begin developing, regardless of the genotype, what’s the phenotype of an individual like this going to be? Female.
what happens to the pronephric duct in males?
under the influence of MIF, the pronephric duct is gone, except for a couple of remnants. One called the utricul (Fig B ”utriculus prostaticus”) and the other the appendix of the testis (Fig B “Appendix testis). No clinical significance of either one, they’re just embryologic vestigial remnants of that pronephric duct.
excretory mesonephric tubules
anastamosing of seminiferous tubules to mesonephric duct (soon to be vas etc)
under action of testosterone
Well, what about the next part of the duct system? Well, here you have the excretory tubules that are left over from the development of the mesonephric duct. And these excretory tubules still retain their connection to the mesonephric duct. And what happens is that the rete testis connect to these excretory tubules, providing a pathway for the spermatozoa that are made in the seminiferous tubules to leave the testes and go into these ducts which are known as the efferent ducts. Efferent meaning away. So the job of the efferent ducts is the connection point from the testes in to this mesonephric duct, which of course, is going to give rise to the epididymis, the vas deferens. All of this will occur under the influence of testosterone.
what type of tissue is mesonephric duct?
intermediate mesoderm
Leydig Cells
turned on by SRY on Y choromosome
Leydig cells, which you’ll learn about later, which are cells that sit in this interstitial area of connective tissue, will begin to synthesize and release testosterone. The development of the male duct system and external genitalia is entirely dependent on the presence of testosterone and its derivatives.
So the presence of testosterone being secreted by the Leydig cells is going to force the development of the gonad and the duct system along the male pathway, while the secretion of MIF from these Sertoli cells will cause the degradation of the paramesonephric duct. All under the influence of this Sex-determining region of the Y chromosome and the testes determining factor.
amniocentesis
14-19 wks
karyotype, AFP, Rh, genetic
hcg in down syndrome?
placental hormone that is increased in down syndrome pregnancy
innervation and embryology of the penis
After the phallus has grown you still have a small problem because the end of the penile urethra is closed by a cord of epithelial cells (Fig C top). And in order to canalize or open up the penile urethra, epithelial cells from the external portion and like little Pac-Men they chew out that epithelial cord opening. And that’s why the innervation of the penile urethra at the glands – ectoderm it hurts, further in it’s endoderm and autonomically innervated.
what does DHT drive the differentiation of?
prostate
external genitalia
two separate vaginal canals?
How would you explain bottom left picture – a uterus with a septum in the center?
What didn’t happen? The septum didn’t degenerate so you end up with a dual uterus.
How about the top picture – two separate vaginal canals?
They both separately touch the urogenital sinus instead of meeting in the center.
genital ridge
You can see the development of that mesonephric kidney attaching to the mesonephric duct. And sitting in the posterior wall, is this large amount (mouse: Fig B “Genital Ridge”) of unsegmented intermediate mesoderm that will eventually give rise to the gonad. So this general area is called the genital ridge. The only thing that’s missing is the germ cells. So this is how things look at about 21 days.
SRY
Germ cells have migrated to the genital ridge:
So, if it’s a male, which is what we’ll talk about first, on the Y chromosome sits a region called the S-determining region of the Y-chromosome (SRY region of the Y chromosome). And it’s responsible for synthesizing what’s been known as the testes determining factor (TDF). A number of genes are involved in this. A number of transcription factors. But in the end, two critical things happen because of this SRY. And what happens is that Leydig cells, which you’ll learn about later, which are cells that sit in this interstitial area of connective tissue, will begin to synthesize and release testosterone. The development of the male duct system and external genitalia is entirely dependent on the presence of testosterone and its derivatives. The second thing that the SRY will control is the secretion from another cell type, a cell type that’s also found in the testes, the cell type is known as Sertoli cells. When I talk to you about the histology of the male reproductive system, we’ll come back to these very, very interesting cells. But for now, you need to know that the Sertoli cells synthesize and secrete a substance called Mullerian Inhibitory Factor (MIF). The sole function of the Mullerian Inhibitory Factor is to suppress the development and cause the degradation of the paramesonephric duct. It’s the paramesonephric duct that we’ll see in a little while, that gives rise to the female reproductive system, ducts, and organs.
So the presence of testosterone being secreted by the Leydig cells is going to force the development of the gonad and the duct system along the male pathway, while the secretion of MIF from these Sertoli cells will cause the degradation of the paramesonephric duct. All under the influence of this Sex-determining region of the Y chromosome and the testes determining factor. So what begins to happen under the influence of testosterone? Well, these primitive sex cords (Fig), which the primordial germ cells are beginning to populate, will actually lose connection to this overlying epithelium. The epithelium will begin to thicken (mouse “proliferating body epithelium”) and become what you’re very familiar with now, the tunica albuginea.
cortical cords in the female
. And then what will happen is these primitive sex cords will actually degenerate entirely and a second wave of sex cords will develop that we call the cortical cords (Fig A). And it is these cortical cords that will come and surround each of the primordial germ cells. That will give rise to the oogonium (Fig B). So this is how the gonad forms.
complete androgen insensitivity
looks completely female from the outside and completely male inside - responsive to T but not DHT
This individual has testicular feminization where the receptors for DHT on the urogenital sinus are not operative. So while the testosterone is being converted by the 5-alpha-reductase to DHT, there are no receptors on the external genitalia, to recognize them.
This was also called a male pseudo-hermaphrodite in older textbooks, but now the preferred term is “disorder of sexual development” (DSD).
Testicular feminization = complete androgen insensitivity
(student: Is MIF still active? Mel: correct, which is why there are no female duct derivatives here)
(student: Would a defect in 5-alpha-reductase have the same effect? Mel: No, because the DHT is going to affect two major things: the prostate gland and the external genitalia. But the duct and the derivatives are responsive to testosterone. So the testosterone itself will drive the development of the mesonephric duct to form your vas deferens, ejaculatory duct, seminiferous tubules.. So you would actually see male duct derivatives internally)
Where are the gonads? They are actually hidden in the inguinal canal – they don’t actually descend.
When you take a look histologically, they’re rudimentary and hyalinized with a lot of connective tissue. In individuals with testicular feminization, the gonads need to be removed surgically – they’re very prone to developing testicular cancer if not.
So what do you do? Can we help him menstruate? No, because there are no female duct derivatives.
thalidomide
morning sickness drug
caused unusual malformations
genital tubercle in males
External genitalia in the indifferent stage, you have the (Fig A) genital tubercle, cloacal fold, and after the anal rectum septum separates it (Fig B), we have the tubercle, the urethral folds and the genital swellings. Under the influence of DHT, what will happen is the genital tubercle will begin to enlarge. As the genital tubercle enlarges those urethral folds begin to be stretched. And as you stretch the folds, they get closer and closer and closer together until they eventually fuse.
chorionic villus sampling
9-13 wks
karytype, Rh, genetic (not AFP - can’t test for neural tube defects!!)
pronephric kidney
When you look at this in a mid-sagittal section, the blue represents that intermediate mesoderm, and during development, and this is the development of the urinary system, you can see how this large amount of intermediate mesoderm begins to segment from cranial to caudal, as the kidney systems being to development. The first one (mouse: Fig A “Segmented intermediate mesoderm”), the pronephric kidney, never really actually makes these excretory units and they usually don’t even attach to this blue mesonephric duct.
Here on the right, you can see it actually says, the vestigial pronephric system (mouse Fig B) – it’s not really functional. But as this begins to degenerate, the next wave of tubules from the mesonephric kidney begins to develop.
mesonephric kidney
Here on the right, you can see it actually says, the vestigial pronephric system (mouse Fig B) – it’s not really functional. But as this begins to degenerate, the next wave of tubules from the mesonephric kidney begins to develop. This will form functional excretory tubules. They will attach to this mesonephric duct. And if you follow the mesonephric duct down inferiorly, of course, it’s going to empty into the urogenital sinus (at one time, it’s going to end up emptying into the bladder). This yellow area (mouse Fig B “ureteric bud”), this outpocketing, of endoderm of the urogenital sinus is called the ureteric bud. And it is responsible for inducing this intermediate mesoderm to form the final, true metanephric kidney. Now during development of the genital system, in the female, all of this goes. But in the male, the caudalmost excretory tubules will be retained along with the mesonephric duct, because it will be critical for the development of the duct system.
what part of female repro is from the urogenital sinus?
All of that is derived from mesoderm. Since the lower half/two-thirds of the vagina comes from the urogenital sinus, it’s going to be derived from endoderm.
Sertoli Cells
. But for now, you need to know that the Sertoli cells synthesize and secrete a substance called Mullerian Inhibitory Factor (MIF). The sole function of the Mullerian Inhibitory Factor is to suppress the development and cause the degradation of the paramesonephric duct. It’s the paramesonephric duct that we’ll see in a little while, that gives rise to the female reproductive system, ducts, and organs.
So the presence of testosterone being secreted by the Leydig cells is going to force the development of the gonad and the duct system along the male pathway, while the secretion of MIF from these Sertoli cells will cause the degradation of the paramesonephric duct. All under the influence of this Sex-determining region of the Y chromosome and the testes determining factor. So what begins to happen under the influence of testosterone?
Reifenstein’s syndrome
. Reifenstein’s syndrome is a little bit different from testicular feminization, which is a complete androgen insensitivity. This is an example of partial androgen insensitivity. And here you can see how while the escutcheon looks completely normal, there is a little bulb over there that when you examine it, is a testes. And the clitoris or penis is (?). So the ambiguous genitalia can go many different ways. There are many syndromes like this and these are examples of varying degrees of partial androgen insensitivity.
Klinefelter’s Syndrome
when you look at an individual with Klinefelter’s Syndrome, phenotypically, they appear male. Little gynecomastia or abnormal breast development in the male. Histologically, their testis aren’t quite right. The key here is when you look at the karyotype. In Klinefelter’s, you have XXY, but there are many other examples of various syndromes that have XXXXY or XXXXXY. The point is that once you have a Y chromosome and the SRY region of that Y chromosome, it doesn’t matter how many X chromosomes are present, it will force the development of a phenotypic male. Klinefelter’s syndrome is just one of many
Down syndrome
trisomy 21
1:1000 births (75-80% spontaneously abort)
life expenctancy is 60 years
40-50% CHD
mental impairment IQ50
no statisitical significant correlation unless mothers were over 35!!
congenital adrenal hyperplasia
The end result that you see phenotypically is actually the result of another problem and that is that the adrenal gland is not putting out sufficient amount of cortisol. And so, with an insufficient amount of cortisol in the blood, the hypothalamic pituitary axis is calling on ACTH to get that cortisol level up. But there’s a deficiency in one of the enzymes making cortisol. So it’s like the little engine that could – you keep stimulating it more and it tries like hell but it can’t and under all of this stimulation the adrenal gland grows and grows and grows. That’s hyperplasia.
And what happens is that all the other hormones that the adrenal gland would normally make, like testosterone, begin to circulate at much higher levels during the development of that external genitalia. So in utero, the development of the external genitalia occurs at a specific time (around 7-8 weeks). The presence of androgens, even though it’s a XX genotype, the presence of androgens will cause the external genitalia to masculinize.
Intermediate mesoderm
And the reason for parietal and visceral has everything to do with your most favorite topic, innervation. But between the paraxial and the lateral plate mesoderm comes to lie a large amount of mesoderm that we call the intermediate mesoderm. The intermediate mesoderm provides for the development of almost the entire urogenital system.
indifferent stage
So in about 4 or 5 weeks of development, you have what we call this indifferent stage. The primordial germ cells have finished schlepping up the dorsal mesentery, populate the genital ridge. And if you look at the embryo at this level, even though the genotype has been determined, the phenotype hasn’t, and this is called the indifferent stage. So whether this is going to be a male or a female, at this stage, you cannot tell. Note the close development of this mesonephric kidney in proximation to the developing gonad. In addition there exists another set of ducts that you know about called the paramesonephric duct which are also derivatives of the intermediate mesoderm.
what gives rise to the seminiferous tubules?
the primitive sex cords (mouse Fig A “testis cords”) , now known as the cortical sex cords, become populated by the primordial germ cells, and these these will give rise to the seminiferous tubules. So the primordial germ cells populate these primitive sex cords. They’re going to form our seminiferous tubules
what leads to trisomies?
nondisjunction - increased by decades of dormancy
mostly think of it in eggs but happens in sperm too!!
vaginal atresia
How about vaginal atresia (top pic) – absence of a vaginal canal?
Many possibilities:
They never touched
Have to deposit something for a successful induction – cells must be secreting a growth factor of some type upon contact to induce. And for vaginal atresia, one could imagine they don’t secrete whatever it is they’re supposed to secrete or they secrete but you’re missing the receptors on the urogenital sinus that would cause the induction.
