T2 L12 Sexual Differentiation Flashcards
What is the prevalence of genital abnormalities?
1 in 4500
What are the 3 main events involved in making a boy/girl?
1) Sex determination during fertilisation
2) Differentiation of gonads in week 5
3) Differentiation of internal and external genital organs after week 5
When is sex determined?
At fertilisation
What determines sex?
Inheritance of X/Y from father
What happens at week 2?
Primordial germ cells arise from the epiblast
What happens to the primordial germ cells?
They migrate to the yolk sac stalk to avoid becoming imprinted
Later return, travelling to genital ridge (next to kidney) and become indifferent gonad
What happens to PGC at the genital ridge?
XX PGCs replicate at the cortex
XY PGCs replicate at the medulla
What does gonad gender decision rely on?
Genetic switches
Hormones
What are the 3 types of genetic switches?
General transcription factors (Wt1, Sf1)
Specific promoters of testis development (Sry, Sox9)
Specific promoters of ovarian development (Wnt-4, FoxL2)
Describe the fate of female PGCs
Female PGCs become oogonia
Describe the fate of sex cord cells
Become granulose which support and nitrify ovum
Describe the fate of the cortex
Become layer of theca cells to secrete androgens before those generated by the follicles
Describe the fate of male PGCs
Become spermatogonia
What does AMH do?
Suppresses female development pathway
Induce cells in intermediate mesoderm to become leydig which then secrete testosterone
Where is the origin of kidney development?
Intermediate mesoderm (reproductive organs also develop here)
Where do the kidneys develop from?
Between somites and lateral plate (each side of aorta)
What are the 3 stages of kidney development?
1) Pronephros
2) Mesonephros
3) Metanephros
What are the 2 sets of paired ducts possessed by embryos of both sexes?
Paramesonephric - Mullerian
Mesonephric - Wolffian
What does the Mullerian duct become in the female embryo?
Oviduct
Uterus
Cervix
Upper part of vagina
What promotes Wolffian duct differentiation in the male?
Epididymis
Vas deferens
Seminal vesicle
What does the genital tubercle consist of?
Urethral groove
Paired urethral folds
Paired labioscrotal swellings
What does DHT stimulate the development of during male development?
Urethra
Prostate
External genitals (scrotum and penis)
What does the genital tubercle become in the male?
Penis
In the male, what forms the spongy urethra?
Fusion of urethral folds
What forms the scrotum?
Labioscrotal swellings
What does the genital tubercle become in the female?
Clitoris
What forms the labia minor?
Urethral folds remain open
What becomes the labia major?
Labioscrotal swellings
What forms the vestibule?
Urethral groove
What kinds of abnormalities can occur?
Chromosomal Hermaphroditism Gonadal dysfunction Tract abnormalities Gonadal descent External genitalia
Give an example of a chromosomal condition
Turner’s syndrome
Klinefelter’s syndrome
What is Turner’s syndrome?
Monosomy XO
99% non-viable embryos
Survivors fail to sexually mature at puberty
Exhibit several physical abnormalities
Diagnosis confirmed through amniocentesis
How frequent is Turner’s syndrome?
1 in 2500 females
Symptoms of Turner’s syndrome?
Short stature Low hairline Shield-shaped thorax Widely spaced nipples Shortened metacarpal IV Small finger nails Brown spots Characteristic facial features Fold of skin Constriction of aorta Poor breast development Elbow deformity Rudimentary ovaries No menstruation
What is Klinefelter’s syndrome?
47, XXY
Birth appear normal
Become infertile
Exhibit some features associated with female development e.g. gynaecomastia
Diagnosis confirmed through amniocentesis
How common is Klinefelter’s syndrome?
1:600-1000 male births
Symptoms of Klinefelter’s syndrome
Taller than average height Reduced facial hair Reduced body hair Breast development Osteoporosis Feminine fat distribution Small testes
What is hermaphroditism?
Condition of having male and female reproductive organs
What are true hermaphrodites?
Extremely rare
Born with both ovarian and testicular tissue (ovotestis)
46 XX (Sry+), 45X (Sry+) & 45X
External genitals may be ambiguous or appear to be female or male
What is the possible cause of true hermaphrodites?
Two ova fertilised by 2 sperm that fuse to form a tetragamtic chimera
What are female pseudohermaphrodite?
46 XX with virilisation due to androgens
Internal sex organs are normal, including ovaries
External appearance and genitals: male
Features: fusion of labia, enlarged clitoris
What are the causes of female pseudohermaphrodite?
Exposure to male hormones prior to birth e.g. from congenital virilising adrenal hyperplasia
What are male pseudohermaphrodite?
46 XY with undervirilisation
External genitals: incompletely formed, ambiguous or clearly female
Some features: blind-ending vagina, absence of breast development, primary amenorrhoea
Testis: normal, malformed or absent
What are the main causes of male pseudohermaphrodite?
Defective androgen synthesis
Defective androgen action e.g. receptor disorder
What is androgen insensitivity syndrome (AIS)?
Testicular feminisation
Affects 1 in 20000-64000 male births
(Male) hormones are normal
Dysfunctional receptor to these hormones
What is leydig cell hypoplasia?
Leydig cells don’t secrete testosterone
Possible reason: body insensitive to LH
External genitalia: normally female / slightly ambiguous
No female internal genitalia (uterus) develops
Describe gonadal dysfunction?
Example: XY gonadal dysgenesis (Swyer’s syndrome)
Associated with XY karyotype
Cause: alteration to Sry gene
External appearance: female (no menstruation)
No functional gonads (no testicular differentiation)
Gonad may develop into malignancy
Give some examples of tract abnormalities
Uterine e.g. unicornuate uterus
Vagina e.g. agenesis
Ductus deferens: unilateral or bilateral absence, failure of mesonephric duct to differentiate
Describe cryptorchidism
May be unilateral / bilateral
Occurs 30% premature, 3-4% term males
Descent may occur during year 1
Describe undescended ovaries
Quite rare
Detected in clinical fertility assessment
What is the most common cause of abnormal external genitalia?
Male hypospadia
1 in 125 live male births
Failure of male urogenital folds to fuse
Outcome: proximally displaced urethral meatus
