L25 Sex chromosomes and sex determination 2 Flashcards
Discordance of phenotypic sex - external genitalia
- bi potential
see onenote
most common
External features start as bipotential
- Female => clitoris
- Male => penis
- Depends on the hormone signals
If structure sees androgens => male structures
Same structures just patterned differently depending if you see hormones or not during early development
Difficult to assign a gender - some where in between
Can you preserve their fertility? Can you preserve the phenotypic outcome?
Hypospadia
see onenote
- ectopic placement of urethral opening
- most common brith defect
- increased by 50% in past 40 years, too fast to be accounted by genetics - must be caused by environment
Hypospadia - hormones
see onenote
- low testosterone
- excess estrogen
- early androgen priming
- surgical repair
- endocrine disruption
E.g. exposed to estrogen through the pill, female does not know she’s pregnant and continues taking the pill
Foetus needs to be exposed to testosterone early on to form proper male structure
Surgery
- Penis needs to expand, would not work if it is covered in scar tissue
BPA
- Bad for health
- Causes sex reversal in frogs if BPA is used on crops
- Endocrine disruptors
Novel model
see onenote
- mutagenesis
Deletion of Leat1; novel lncRNA
see onenote
Mutation in this gene causes anal-rectal malformation
- Often lethal in mice and human
Don’t code for protein but regulate their neighbouring genes
- Leat1 regulates Efnb2
Leat1 and EphrinB2
see onenote
Leat1 expression overlaps with ephrinB2 - appropriate interaction
Leat1 function
see onenote
- leat1 binds ephrinB2
- estrogen suppresses leat1 and ephrinB2 (in a leat1 dependent manner)
Estrogen in the environment causes hypospadia
- When exposed to estrogen, 50% reduction in leat1 expression
- Leat1 regulates ephrinB2, level of leat1 drops => level of ephrinB2 also drops
Leat 1 is expressed in human UPE and variable in mild hypospadias patient
see onenote
Leat1 conserved in humans, mice, wallabies
- Unusual for lncRNA
- Expressed in human penis
- Hypospadia patients, almost had no leat1 expression
- Environmental toxin interrupting developmental program
Leat1 expressed alongside EfnB2 in human urethral plate
expression variable in mild hypospadias patients
Leat1 mechanism of action
see onenote diagram
Discordance of phenotypic sex - internal reproductive tract
see onenote
Initially starts at indifferent structures
- If internal plumbing don’t see any hormones => passively develop into female reproductive system (wolffian duct will disappear)
- mullerian duct will develop into fallopian tubes and upper third of the vagina, lower third vagina is independently developed
Male
- Need testosterone to differentiate
- Testis produces anti-mullerian hormome to regress female tract (need to get rid of female plumbing useless for male to having fallopian tubes etc. inside their body cavity, BUT does occur - dangerous) - see “a” diagram, could lead to cancer
Hermaphroditism vs Pseudohermaphroditism
see onenote
AMH or AMH-receptor
inadequacy
- persistent mullerian duct syndrome
- failure of testicular descent
Defects in steroidogenesis or androgen action
- various phenotypes
Testicular descent
see onenote
- testes migrate from abdomen to scrotum and inguinal canal
Failure of descent
- cryptorchidism
- no sperm production
- high risk of testicular cancer
Fixes itself in about 90% of cases
- Testes will descend in the first 6 months
- If after 6 months, descent hasn’t occurred, has to go inside to pull them out
- If abdominal testes remains inside, will turn into aggressive cancer, abdominal cavity is 2 degrees warmer - must be removed early on
- Testes descent is a highly hormonal dependent process
Persistent Mullerian Duct Syndrome
see onenote
- rare
- affects genetic males
- autosome recessive
- mutations in AMH, AMHR
- almost always cryptorchid
Testes connected to fallopian tubes and vagina
- Can remove all the female structures and move testes down into scrotum
Lots of surgery
Congenital adrenal hyperplasia (CAH)
see onenote slides
- autosomal recessive
- defect in 21-hydroxylase gene
- reduced cortisol and aldosterone
- increased adrenal androgen secretion
- affected female foetus is masculinised
- but phenotype is intersex
- genital surgery => female appearance but what about brain sex?
Complete androgen insensitivity syndrome (AIS) - phenotype
see onenote slides
Able to produce testosterone but body does not respond to signal
XY males but can’t detect testosterone
- Will completely feminise
Usually show up early in life
- Girls fails to menstruate
- Only find out at about 15 years old
Complete androgen insensitivity syndrome (AIS) - laboratory
see onenote
- XY karyotype (SRY positive)
- AR (androgen receptor) gene mutation usually detected (allows carrier identification, prenatal diagnosis)
- adult blood levels: high LT and T, slightly high FSH
- oestrodiol level higher than normal male, less than adult female
Gonad will develop as testis
- Produce T but as no androgen receptor => male plumbing cannot form (wolffian duct will disappear)
- AMH is fine, AMH (anti-mullerian hormone) receptor is fine => will lose female internal plumbing as well
Complete androgen insensitivity syndrome (AIS) - clinical
see onenote
- relatively tall, normal breast development
- absent/sparse body hair
- no uterus - no period
- short vagina
- inguinal/abdominal testes
partial forms have reduced AR activity or androgen synthesis => intermediate phenotypes
5alpha- reductase deficiency
see onenote
- clinical: present as females at birth
- puberty: masculinisation of body, clitoral enlargement, male pattern body hair
- lab: 5AR mutation
When they hit puberty, they turn into boys
Nothing abnormal until puberty
- Completely masculinises
- They have mutation in enzyme that converts T to dihydrotestosterone (DHT)
- DHT ten times more potent than T
- As you undergo development you feminise due to lack of DHT (T by itself is not enough to cause male development)
- At puberty, testis pumps out lots of T => become boys, don’t need DHT as testis are pumping out enough T (huge surge of T)
Discordance of Brain Sex
see onenote slides
- aromatase enzyme in many brain areas (only affects males during development)
- non-aromatisable androgens like DHT do not have same effect on brain as testosterone
- oestrogen masculinise brain
- anti-oestrogen can block some effects of T on brain sex
- effects via cell division in some cells and apoptosis in others
Patterned by hormones
- Presence of estrogen => masculine behaviour
- Lack of hormones => female behaviour
- Sexual identity and sexual preference, controlled by different parts of the brain
Give female brain DHT, DHT cannot be converted to estrogen
Give female brain T, T converted to E => male brain
Development of gender identity
see onenote
3 stages:
- gender identity 1-3 years
- gender stability 3-4 years
- gender constancy 5-6 years
Gender identity is distinct from homosexuality
Sex identification is fundamentally very important, allows appropriate assimilation
Can your brothers make you gay?
see onenote
- each additional older brother increases odds of homosexuality by 33%
- effect restricted to biological older brothers
- only true for right-handed homosexual men
- confirms sexual orientation sex before birth
Female carrying the child doesn’t see foetal androgen in their life time
- Gestating a boy, will suddenly see foetal androgen, will develop antibodies to it
- More sons => more aggressive immune system, more antibodies produced, binds to androgens and aren’t able to masculinise the baby
Gender Dysphoria
Different from homosexuality where men still identify as men; women as women
cognitive sex =/ biological sex
- cross dressing
- transsexual
- gender identity disorder
- hormones and sex reassignment surgery
- other gender variant issues
Very damaging for the individual
- Feeling like you are the opposite sex
- If you treat them early on before puberty, could possibly sex reverse them
- Australia allows for parents to opt for aggressive hormonal treatment and surgeries for their children before they turn 18
Gender dysphoria in DSD and prenatal exposure to androgens
see onenote
XX congential adrenal hyperplasia
- 5.2% CAH girls vs0.003% non-CAH girls
XY complete androgen insensitivity syndrome
- gender dysmorphia reported but rare
XY partial androgen insensitivity syndrome
- gender dysmorphia high (25%) whether raised male or female
The genderless child
see onenote
Brain sex beyond hormones
see onenote slides
Move SRY gene to autosomal chromosomes
What happens if you are XY male vs XX male
What happens if you are XY female vs XX female
- How does it effect how our brain works/functions ?
- Most things were the same, differences in densities of certain neurons
Independent of hormones
- Intruder directed aggression, XY chromosome regardless of whether you were male or female (classic male aggression directed behaviour), could gene responsible for this be on Y chromosome
- Pup retrieval, usually seen in females, if you are a XX male will do pup retrieval process
- Other things on X chromosome which are responsible for behaviour
Difficult decisions required in DSD management
see onenote
- gender assignment/concordant with gender identity
- genital surgery on infants, unable to consent for themselves
- removal/or not of gonads - cancer risk
moving towards holistic approach where we have clear diagnoses and data from clinicians and psychologists to maximise patient outcomes
