Sexual Differentiation And Disorders Flashcards
What is the definition of sexual determination?
→ Genetically controlled process dependent on the switch on the Y chromosome
What is sexual differentiation?
→ The process by which internal and external genitalia develop as male or female
What does gender depend on?
→ A switch gene in the Y chromosome
What is genotypic sex?
→ XY
→ XX
What is gonadal sex?
→ Testes
→ Ovaries
What is phenotypic sex?
→ outward appearance
What is Legal sex?
Passport/birth certificate
What is gender identity?
→ How you feel / not always the same as phenotypic
What is the first event that occurs that determines sex?
→ Genetic signal which then form testes or ovaries
What gene creates the testes?
→ The SRY gene
In the absence of the Y chromosome what develops?
→ Ovaries
What does SRY mean?
→ Sex determining region
When does the SRY region switch on and what happens when it is switched on?
→ During embryo development in > week 7
→ makes gonad into testis
What two types of cells are in the testis?
→ Sertoli cells
→ Leydig cells
What do Sertoli cells make?
→ Produce anti mullerian hormone
What do Leydig cells make?
→ Testosterone
What is SRY?
→ A transcription factor that causes self transcription
What happens after fertilization (gonads)?
→ A pair of gonads develop which are bipotential
What is the precursor of gonads derived from?
→ Somatic common mesenchymal tissue precursors called genital ridge primordia
on posterior wall of lower thoracic lumbar region
What do the genital ridges become?
→ Ovaries or testes
What does the Mullerian duct become?
→ Uterus
→ Uterine tubes
→ Upper third of vagina
What does the Wolffian duct become?
→ Vas deferens
→ Prostate
What are the 3 types of cells that invade the genital ridge?
→ Primordial germ cells
→ Primitive sex cords
→ Mesonephric cells
What do primordial germ cells become?
→ Sperm or oocytes
What do primitive sex cords become?
→ Sertoli cells
→ or Granulosa cells
What do mesonephric cells become?
→ Leydig cells
→ Theca cells
Describe primordial germ cell migration
→ Small clusters of PGC cells in the epithelium of the yolk sac expand at 3 weeks
→ Migrate to the connective tissue of the hindgut to the region of the developing kidney and onto the genital ridge
Describe what happens to primitive sex cords in the male
→SRY expression
→Penetrate the medullary mesenchyme and surround the primordial germ cells to form testis cords
→Eventually become sertoli cells which express anti Mullerian hormone
Describe what happens to primitive sex cords in the female
→No SRY expression
→Sex cords are ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around PGCs
→become granulosa cells
What type of structures do the sex cords form?
→ Tubular structures with germ cells inside of them
Where do mesonephric cells originate from?
→ Mesonephric primordium which are lateral to the genital ridges
What do mesonephric cells in males act under the influence of?
→ Pre sertoli cells that are already there and express SRY
What do mesonephric cells form in males?
→ Leydig cells - synthesize testosterone- do not express SRY themselves
→ Basement membrane
→ Vascular tissue
What does the basement membrane form in males?
→ Seminiferous tubules and rete-testis
What do mesonephric cells form in females?
→ Theca cells
→ Vascular tissue
What do Leydig cells synthesize?
→ Testosterone
What do Theca cells synthesize?
→ Androstenedione which is a substrate for estradiol production
What hormone does the male gonad produce that the female gonad does not?
→ Anti mullerian hormone
What do Sertoli cells make and what does this do to the Leydig cells?
→ Anti mullerian hormone
→ causes Leydig cells to synthesize testosterone
Give a summary of the 3 types of cells in males and what they produce?
Primary germ → Sperm cells
Primitive sex cords → Sertoli cells (AMH, SRY)
Mesonephric cells → Leydig cells (testosterone)
Give a summary of the 3 types of cells in females and what they produce?
Primitive germ → oocytes
Primitive sex cords → Granulosa cells (Estradiol)
Mesonephric cells → Theca cells (androstenedione)
What are Mullerian ducts inhibited by?
→ AMH
What are wolffian ducts stimulated by and why do they regress?
→ Regress if there is lack of stimulation by testosterone
→ Stimulated by testosterone
Where is testosterone converted?
→ Genital skin
What is testosterone converted into?
→ dihydrotestosterone
What enzyme is used to convert testosterone?
→ 5areductase
What form of testosterone is more potent?
→ dihydrotestosterone
Describe how DHT cause differentiation of male external genitalia
→ Clitoral area enlarges into penis
→ Labia fuse and become rugated to form scrotum
→ Prostate forms
Why is there no differentiation of female genitalia into male genitalia if 5a reductase is present?
→ there is no substrate (testosterone)
Flowchart of sequence leading to differentiation of external male genitalia
SRY is expressed with a Y chromosome ↓ Sertoli cells form ↓ Testis formation occur ↓ Sertoli cells secrete AMH ↓ Regression of Mullerian duct ↓ Leydig cells secrete testosterone ↓ Growth of Wolffian duct ↓ Testosterone is acted on by 5 a reductase to DHT ↓ development of male external genitalia
Flowchart of sequence leading to differentiation of external female genitalia
no Y chromosome ↓ no AMH ↓ Mullerian ducts grow ↓ Ovary doesn't produce testosterone ↓ Wolffian ducts regress ↓ External female genitalia develop
What is gonadal dygenesis?
→ Sexual differentiation is incomplete
→ Missing SRY in male or partial or complete deletion of X in female
What is sex reversal?
→ Phenotype does not match genotype
→ may be male genotypically but externally female
What is intersex?
→ have some components of both tracts or ambiguous genitalia
→ Sex of infant is difficult to determine
What is androgen insensitivity syndrome?
→ XY individual making testosterone but it has no effect
What is a clue to androgen insensitivity?
→ lack of body hair
→ Amenorrhoea
What occurs in a 5 alpha reductase deficiency?
→ Testes form and AMH acts so Mullerian ducts regress, Wolfian ducts develop
→ Internal structures form
→ External structures do not develop
→ Appear mainly female
What is turner syndrome?
→ When there is the absence of an X chromosome
What are the characteristics of turner syndrome?
→ Streak ovaries
→ ovarian dysgenesis
→Uterus and tubes are present but small, other defects in growth and development.
→
How does congenital adrenal hyperplasia work?
→ when an XX female is exposed to high levels of androgens in utero
What does the adrenal gland make?
→ Steroids
What are the main steroids that the adrenal gland makes?
→ Aldosterone and cortisol
Where are the rest of the steroids made and what are they called?
→ In the gonads
→ Testosterone
→ progesterone
→ Estrogen
What is the structure of cholesterol?
→ 3 six sided rings
→ one 5 sided ring
What is the difference between the estrogens?
→ THe number of OH groups on them
What happens if 21 hydroxylase doesn’t work?
→ Cortisol not produced
→ More ACTH produced (negative feedback)
→ ACTH causes cholesterol to be taken up
→ Cholesterol is converted into androgens instead
What happens to girls when 21 hydroxylase doesn’t work in utero?
→ Increase in testosterone
→ Growth of wolffian duct
→ External genitalia are male
What is the treatment for 21 hydroxylase deficiency?
→ Glucocorticoid
Describe how estrogens are made
→Cholesterol is imported into the cell and has the carbons from carbon 21-27 cleaved
→ it becomes prenenolone (progestagens) which has 21 carbons and two carbons are removed
→ this makes androgens which have 19 carbons and another carbon is removed
→this forms estrogens which have 18 carbons
What does 21 hydroxylase do?
→ Convert cholesterol into cortisol and aldosterone
Where is the SRY gene found on the chromosome?
close
to the end of the short arm of the human Y chromosome
What is the pseudoautosomal region on a chromosome?
Homologous sequences of nucleotides on the X and Y chromosomes. Genes inherited just like any autosomal genes
Compare what Sertoli and granulosa cells form
→Sertoli cells form long tubes with primordial germ cells inside them
→Granulosa cells form clumps around primordial cells
What are the features of androgen insensitivity syndrome?
→Testes form and make AMH so Mullerian ducts regress.
→No differentiation of Wolffian ducts
→No external male genitalia
→Dihydrotesterone is made and because it binds to same receptors as testosterone, its not detected
How is AIS diagnosed?
→Ultrasound scan and karyotype with male levels of androgens.
→Never responded to androgen so appear and often feel female.
What happens in puberty of those with 5-a-reductase deficiency?
→Need to assess potential as high testosterone level which will occur at adrenarche
→puberty may induce virilisation.
What does Turner syndrome show about X-inactivation?
It isn’t the entire X-chromosome that is switched off.
→There are pseudo autosomal regions still on required for ovarian development
What does the severity of Turner’s syndrome depend on?
→when the X-chromosome is switched off. If switched off at one cell stage then it would be most severe. But if lost later on then there a mixture of two Xs and one Xs
What can be lethal in CAH?
→salt wasting due to lack of aldosterone
What are the features of CAH?
→No SRY so no testes and no AMH.
→Mullerian ducts remain.
→Masculinised external genitalia,
→androgen levels not usually high enough to fully rescue Wolffian ducts.
