SEXUAL DIFFERENTIATION: HOW TO MAKE A BOY OR A GIRL Flashcards
Introduction
• Prevalence of genital abnormalities: 1 in 4500. some could be very subtle and some could be very very subtle.
. An article talks about 2 new born babies with no names; baby A and baby B. They were both genetically male which means they have an XY karyotype. However, they did have abnormalities of their external genitalia and therefore doctors in the past use to advice their parent to say that it’s much easier to cut the remnant of a penis and turn it into a vagina than the other way round. so they will just do the surgery, give hormones and advice the parents to raise those kids as females.
- baby A was quite happy, in her twenties and married, however, she cannot have children because she does not have a uterus but at least have a normal happy life.
- baby B; never happy, differed years of depression to try and reverse and the doctors later started testosterone treatment and is not a man.
- the doctors are at fault for thinking to just give a hormone and surgery at the begining.
What makes a boy/girl involves 3 main events
(1) Sex determination which happens during fertilization
(2) Differentiation of gonads, i.e the testes or the ovaries which takes place around week 5
(3) Differentiation of the internal and external genital organs, which takes placer after week 5
Sex determination
• Sex is determined at fertilization (when you have the gametes coming together)
- if its an XX, you will have a genetically female embryo
• Inheritance of X/Y its gonna be male
The X and Y chromosomes, also known as the sex chromosomes, determine the biological sex of an individual: females inherit an X chromosome from the father for a XX genotype, while males inherit a Y chromosome from the father for a XY genotype (mothers only pass on X chromosomes).
what happens after fertilisation
when the egg is fertilised, it undergoes a series of cleavage, it doesn’t start to expand and divide because at this stage it still has to go through the uterine tubes. it divides but actually not increase in size which is what we call cleavages until it becomes a morulla which then becomes the embryo which at about first week or 2 wks its just a flat plate of cells until they undergo a series of fold.
Gonad origin & diff
AT weeks 2, a series of cells will migrate from the epiblast and this particular group of cells will become the primordial germ cells (PGCs) and they are the ones which are gonna become our genital gonads.
At this stage, they are still called pluripotent which means that they can become any type of cell depending on whatever chemical signals or genes that are present. they could become muscle, bone , tendon etc.
because of this, these cells actually migrate away from the developing embryo, into the yolk sac and they stay there for a couple of weeks.
they stay there because at this stage there is a lot of chemical signals and gene expression dictating all of the rest of this population of cells to either become heart, lungs or any other type of tissue.
-2 weeks later, they then migrate back and move in next to the developing kidney on a place called the genital ridge and here they will become the indifferent gonads.
Gonad origin & diff cont
- if we look at the embryo here, we can see the developing kidney and genital ridge. if we just make a little section in the area, you will see that you’ve got the developing aorta, and you have the kidney on the lateral side.
- about week4, it carries on to increase in size and then depending on genetic switches or hormones, it will either go into an ovary at 20 weeks or the testes a few weeks earlier than that.
- one thing that differentiates between the male and female is that the primordial germ cells will replicate at the cortex in the ovary, in the males, they are actually produced from the cortex and they migrate on to the medulla before they leave through the efferent duct tubes.
Gonad gender decision relies on?
1. Genetic switches
2. Hormones
Genetic switches involved in the process of gonad gender decision
There are a lot more genes involved in the process but you only need to know about the below list of genes;
1. general transcription factors,
e.g. Wt1, Sf1
*of these genes are not active, if they don’t express, then the gonads do not develop. if they do develop, you do need additional genes to say they are gonna become a male i.e SRY OR SOX9 genes.
2. specific promoters of testis development
e. g.
a) sex-determining region Y gene which (Sry) which is the sex determining region of the Y chromosome.
b) Sox9
3. specific promoters of ovarian development
e.g. Wnt-4, FoxL2
Fate of gonad cell lines
- We can see our urogenital ridge becoming our bipotential gonad (testes or ovary), there are three main population of cells within this gonad.
1. the ones that will produce the garment (internal theca cells in females and ley dig cell in male)
2. primordial germ cells (oocyte in females and pro spermatogonial cell in the male)
3. supporting cell precursors (follicular cells in females and Sertoli cells in the male)
Fate of gonad cell lines in females
- Female premodial germ cell are the oogonia (primary oocytes)
- Female Sex cord cells are the granulosa (support and nutrifying the ovum)
- Cortex => layer of thecal cells => secrete androgens before those generated by the follicles
Fate of gonad cell lines in males
- Male Premodial germ cells are spermatogonia
- because of the Sry, they will influences the definition + identity of Sertoli cells + secretion of AMH (Anti-Müllerian Hormone)
- AMH supresses female development pathway
- AMH induce cells in intermediate mesoderm to become leydig => secrete testosterone
Origin of Kidney development
Although the kidney is part of the urinary system, it links with urinary system. the kidney development undergoes 3 main stages.
Origin: intermediate mesoderm (as the reproductive organs)
• Where: between the somites and lateral plate (each side of the aorta)
3 Stages:
1- Pronephros - the kidney starts developing and dies soon after.
2- Mesonephros - will develop, work for a little while and then degenerate. leaves remnants behind. these remnants are then hijacked by the reproductive system.
3 - Metanephros - becomes kidney
what stage does the kidney really develop
Metanephros stage. (the final stage)
This takes place in an area between the somite and the lateral plate. what we call the intermediate mesoderm.
-we can see our developing spinal cord shown in blue , the paraxial mesoderm and lateral mesoderm.
(you don’t need to learn this for the KT).
Kidney development
-here is the embryo cut from top to bottom, you can see the pro nephrons which will not work at all, it develops and degenerate soon after you can see our mesonephros that will only work for a little while and degenerates as well but they leave a duct called the mesonephric duct.
Recap
• We have a single set of Gonads that are indiferent (at the start)
• They are Linked to kidney development
• Its The middle stage of kidney development (mesonephros) that leaves behind some remnants/ducts that become integral part of the reproductive system
Internal genital organs
• Begin differentiation at about week 8, after the gonads have already differenciated.
-unlike the gonads where you only have a single pair that becomes testes or ovaries. with internal ducts there is the same primordial structure meaning that whether you are going to become male or female, you have all the structure that will be either make or female together and then you just get rid of whatever pathway the genes are not associated with.
for example, if I am male, I would have been born with all the structures that will develop into a uterus, a vagina, fallopian tubes etc and then they get rid of.
… embryos of both sexes possess two sets of paired ducts at the start:
1. paramesonephric a.k.a. Müllerian
2. mesonephric a.k.a. Wolffian
Internal genital organs
- you have 2 sets, if you are going to in that female pathway, you get rid of the mesonephric ducts (blue line) and you retain the red ones (Mullerian ducts).
- you keep them because you do not have anti-Mullerian hormone. that Mullerian duct is then what’s gonna become the fallopian tubes, uterus, the upper part of the vagina, cervix etc.
- what happens for the males is that the presence of AMH (antimullerian hormone) is gonna suppress the Mullerian duct and at the same time, production of testosterone is gonna promote the development of the Wolffian duct.
- these wolfian ducts will then become the ;
1. epididymis
2. vas deferens
3. seminal vesicle
External genital organs
- we are all born with the same genital structure called the genital tubercle, this midline swelling at the front of the pubic bone.
- this will contain the urethral grove which is an opening in the purple colour, you have the urethral fold bordering that grove and at the side of that we have the red labioscrota swelling.
- all this together is what we call the genital tubercle.
if you are on the pathway to become a male;
some of the testosterone is gonna be converted into DHT ( dihydrotestosterone ) .. this in turn is what stimulates the development of the •urethra, prostate and external genitals (scrotum and penis)
- your genital tubercle is gonna increase greatly in size to become the penis. your urethral fold is gonna fuse together encircling the urethra.
the labial scrotal swelling also fuse together to become the scrotum.
Turner’s Syndrome
There are several different signals that will demonstrate the presence of turners but the most common is RUDIMENTARY GONADS (underdeveloped gonads), lack of breast development, and you can see a picture of the Karyotype where the y chromosome is not present.
Another chromosomal abnormality is the; Klinefelter’s Syndrome.
- The karyotype os gonna be 47 with 3 sex genes instead of 46, (XXY)
- Afects 1 in 600-1000 male births (does not affect females)
- Birth appear normal (undetected)
- They Become infertile
- They Exhibit some features associated with female development (e.g. gynecomastia)
- Diagnosis confirmed through amniocentesis
Hermaphroditism
Named after the offspring of the Greek gods Hermes and Aphrodite. there are 3 examples;
1• True hermaphrodite
2• Female pseudohermaphrodite
3• Male pseudohermaphrodite
(note: these colloquial terms are used for your understanding only and not actually used in the medical profession)
True hermaphrodites
•Extremely rare
• Born with both ovarian and testicular tissue (ovotestis)
• possible cause; This can happen to say imagine there is an egg or 2 eggs like twins that fertilise by 2 different sperm are fused together becoming what we call tetragametic chimera. they can have a presence of - 46XX (SRY+), 45X (SRY+) and 45X. so a mixture of these genes in one person.
• External genitals may be ambiguous, or appear to be female or male
Female pseudohermaphrodite
•46, XX with virilization (due to androgens)
-genetically female but has characteristics of males
- Internal sex organs are normal, including ovaries
- but the External appearance and genitals are more males than females
- Features: fusion of labia; enlarged clitoris looking more like a penis
• Possible cause: during development, the embryo exposure to male hormones prior to birth (e.g. from congenital virilizing adrenal hyperplasia)
Male pseudohermaphrodite
- genetically male but not to the same level of virility.
- so a male with women stuffs not heir body.
• 46, XY with undervirilization
• External genitals: incompletely formed, ambiguous or clearly female
• Some features: blind-ending vagina, absence of breast development, primary amenorrhea (no period).
• Testis: normal, malformed or absent
• Main causes:
- defective androgen synthesis
- defective androgen action (e.g. receptor disorder). either you have no production of androgens or you have androgens that are doing what they are not supposed to do. f
Tract abnormalities
You could have the internal ducts failing to develop. Some examples:
• Uterine: e.g. unicornuate uterus
• Vagina: e.g. agenesis
• Ductus Deferens: unilateral or bilateral absence, failure of mesonephric duct to differentiate
*cornuate stands for horn.
*unicornuate means it only has 1 horn
External genitalia
The most common: male hypospadias
- 1:125 live male births
- Failure of male urogenital folds to fuse
• Outcome: proximally displaced urethral meatus
*surgery is the solution for this patient nd the nerve that needs to be blocked is the pudendal nerve.
