Ambiguous Genitalia: Genes or Environment Flashcards
What is the difference between sex determination an sex differentiation?
Determination - translates chromosomal/genetic sex to gonadal sex.
Differentiation - confers gonadal sex to phenotypic/genital sex.
n.b. that genetic, gonadal and phenotypic sex dont always correspond!
How is sex determined in mammals, birds and reptiles?
Mammals is chromosomal
heterotypic = male
homotypic = female
Birds it is opposite (ZZ-male, ZW-female)
Reptiles is temperature
Name some common disorders of chromosomal sex.
XX male (SRY translocation to an X chromosome)
XY female - Swyer’s syndrome(SRY deficient)
XO female - Turner’s syndrome
XXY male - Klinefelter’s syndrome
What is the jost principle?
Studies of freemartin cows shows that male hormones masculinised the female. This lead to the thinking that female is the default pathway.
Describe the indifferent external genitalia and how this forms the male and female genitalia.
Urethra
Vaginal Orifice - vaginal orifice
Inner labiosacral Folds - phalus/labia minora
Outer labiosacral folds - scrotum/labia majora
Genital tubercle - glans/clitoris
What is the raphe penis?
A fusion on the ventral aspect of the penis corresponding to the fusion of the inner labiosacral folds.
Which ducts persist in the male and female?
Male - wolffian duct
Femal - Mullerian duct
What do the following form?
a) wolffian
b) mullerian
a) epididymis, vas deferens and accessory sex glands
b) oviducts, uterus/uterine horns, upper 2/3 vagina
How is the differentiation of the male and female phenotypes established in terms of the ducts that must persist?
Female - wolffian duct degenerates of its own accord
Male - Testosterone stabilises the wolffian duct whilst AMH breaks down the mullerian structures.
n.b. 5a-DHT is needed to develop male external genitalia.
Describe AMH and how it achieves its effect.
Part of TGFb superfamily, works via AMHR2 in conjuction with ALK2/3/6 in combination. This receptor complex has intrinsic serine/threonine kinase activity.
Where is AMH synthesised?
SERTOLI cells of the foetal testes.
How might persistent mullerian duct syndrome come about?
Defects in AMH, AMHR2 or ALK receptor defects.
Where is testosterone synthesised?
Leydig cells of fetal testes.
What is testosterones affinity with the androgen receptor?
Intermediate - it can only stimulate differentiation of the internal genitalia.
How and where is 5a DHT synthesised?
Genital skin fibroblasts by action of 5a-reductase type 2.
What are the functions of 5a DHT?
Growth of internal genitalia
Differentiation of external genitalia. and secondary sexual characteristics
What is the action of 5a-reductase enzymes?
Addition of H to C5 by removal of the C4=C5 bond.
Why is 5aDHT the most potent androgen?
High AR affinity
Decreased “off-rate” from AR
Activates the receptor more quickly
Stabilised ligand-receptor complex
What are the functions of testosterone?
negative feedback on LH/FSH
spermatogenesis
differentiation of wolffian structures
What is the difference in function of type 1 and type 2 5a-reductase?
1-makes soluble for excretion in urine or sweat
2-makes the testosterone more potent.
How could androgen insensitivity syndrome come about?
- Failure of androgen synthesis
2. Defect of androgen receptor
Why would it be strange to see low levels of androgens, such as in AIS?
Androgens normally have a +ve feedback effect on androgen synthesis.
What are the equivalents of the sertoli and leydig cells in the female?
Sertoli - granulosa
Leydig - theca
Summarise the cells in the male that produce the male hormones needed for sex differentiation.
AMH - sertoli cell
testosterone - Leydig
5a DHT - genital skin fibroblasts
