L11 Sexual differentiation Flashcards
Prevalence of genital abnormalities
1 in 4500
3 main events in sexual differentiation
(1) Sex determination, during fertilisation
(2) Differentiation of gonads, week 5
(3) Differentiation of internal and external genital organs, after week 5
Sex determination (2)
Sex is determined at fertilisation
Inheritance of X/Y from father
Gonad origin and differentiation (5)
At week 2 primordial germ cells (PGCs) arise from the epiblast
PGCs are pluripotent
PGCs migrate to yolk sac stalk to avoid becoming imprinted
Later return, travelling to the genital ridge (next to kidney) and become the indifferent gonad
At genital ridge: XX PGCs replicate at cortex; XY PGCs replicate at the medulla
Gonad gender decision relies on? (2)
Genetic switches
Hormones
Genetic switches (3)
General transcription factors
e.g. Wt1, Sf1
Specific promoters of testis development
e.g. Sry, Sox9
Specific promoters of ovarian development
e.g. Went-4, FoxL2
Fate of gonadal cells in females (3)
Female PGCs => oogonia (primary oocytes)
Sex cord cells => granulosa (support and nutrifying the ovum)
Cortex => layer of thecal cells => secrete androgens before those generated by the follicles
Fate of gonadal cell lines in males (4)
Male PGCs => spermatogonia
Sry influences definition + identity of Sertoli cells => secretion of AMH
AMH surpasses female development pathway
AMH induce cells in intermediate mesoderm to become Leydig => secrete testosterone
Kidney development: origin
Intermediate mesoderm (as the reproductive organs)
Kidney development: where
Between the somites and lateral plate (each side of the aorta)
Kidney development: 3 stages
Pronephros - disappears soon after
Mesonephros - leaves remnants, leaves behind ducts that become integral part of the reproductive system
Metanephros - becomes kidney
Internal genital organs
Begin differentiation at about week 8 formed from a priori identical primordium structures i.e.
embryos of both sexes possess two sets of paired ducts at the start:
- paramesoneohric aka Mullerian
- mesonephric aka Wolffian
Internal genital organs: female
In female embryo: Mullerian duct is kept due to the absence of AMH
Mullerian duct
- oviduct
- uterus
- cervix
- upper part of the vagina
Internal genital organs: males
In male embryo:
- AMH causes Mullerian duct regression
- Testosterone promotes Wolffian duct differentiation
Wolffian duct
- Epididymis
- Vas deferens
- Seminal vesicle
External genital organs
At first embryos of both sexes show an elevated midline swelling - genital tubercle
Tubercle consists:
- urethral groove (opening into the urogenital sinus)
- paired urethral folds
- paired labioscrotal swellings
External genital organs: Male
Some testosterone is converted into dihydrotestosterone (DHT)
DHT stimulates development of the urethra, prostate and external finites (scrotum and penis)
Genital tubercle => penis
Fusion of the urethral folds => spongy urethra
Labioscrotal swellings => scrotum
External genital organs: female
Absence of DHT
Genital tubercle => clitoris
Urethral folds remain open => labia minor
Labioscrotal swellings => labia majora
Urethral groove => vestibule
Types of abnormalities (6)
Chromosomal
Hermaphroditism
Gonadal dysfunction
Tract abnormalities
Gonadal descent
External genitalia
Chromosomal: Turner’s syndrome
Monosomy, XO
1:2500 female (does not affect males)
99% non-viable embryos
Survivors fail to sexually mature at puberty
Exhibit several physical abnormalities
Diagnosis confirmed through amniocentesis
Physical abnormalities in Turner’s syndrome
Short stature
Low hairline
Widely spaced nipples
Poor breast development
Brown spots (nevi)
Constriction of aorta
Chromosomal: Klinefelter’s syndrome
47, XXY
1:600 - 1000 male births (does not affect females)
Birth appear normal (undetected)
Become infertile
Exhibit some features associated with female development (e.g. gynaecomastia)
Diagnosis confirmed through amniocentesis
Physical abnormalities in Klinefelter’s Syndrome
Taller than average height
Reduced facial hair
Reduced body hair
Breast development
Osteoporosis
Feminine fat distribution
Small testes
Hermaphroditism
Named after the offspring of the Greek gods Hermes and Aphrodite
True hermaphrodite
Female pseudohermaphrodite
Male pseudohermaphrodite
True hermaphrodite
Extremely rare
Born with both ovarian and testicular tissue (ovotestis)
46XX (SRY+), 45X (SRY+) and 45X
Possible cause e.g. two ova fertilised by two sperm that fuse to form a tetragametic chimera
External genitals may be ambiguous, or appear to be female or male
Female pseudohermaphrodite
46, XX with virilisation (due to androgens)
Internal sex organs are normal, inc. ovaries
External appearance and genitals: male
Features: fusion of labia; enlarged clitoris
Possible cause: exposure to male hormones prior to birth (e.g. from congenital virilising adrenal hyperplasia)
Male pseudohermaphrodite
46, XY with undervirilisation
External genitals: incompletely formed, ambiguous or clearly female
Some features: blind-ending vagina, absence of breast development, primary amenorrhea
Testis: normal, malformed or absent
Main causes:
- defective androgen synthesis
- defective androgen action (e.g. receptor disorder)
Male pseudohermaphrodite: AIS
Androgen Insensitivity Syndrome
Aka testicular feminisation
Affects: 1:20000-64000 male births
Male hormones are normal
Dysfunctional receptor to these hormones
Male pseudohermaphrodite: Leydig cell hypoplasia
Lydia cells do not secrete testosterone
Possible reason: body insensitive to LH
External genitalia normally female/slightly ambiguous
No female internal genitalia (uterus) develops
Gonasal dysfunction
E.G. XY gonadal dysgenesis aka 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
Some examples of tract abnormalities
Uterine e.g. unicornuate uterus
Vagina e.g. genesis
Ductus Deferens: unilateral or bilateral absence, failure of mesonephric duct to differentiate
Gonadal descent
More apparent and common in males (cryptorchidism) than on females (undescended ovaries)
Cryptorchidism
May be unilateral/bilateral
Occurs 30% premature; 3-4% term males
Descent may take place during year 1
Undescended ovaries
Quite rare
Detected in clinical fertility assessment
External genitalia
Most common: male hypospadia
1:125 live male births
Failure of male urogenital folds to fuse
Outcome: proximally displaced urethral meatus
The brain and behaviour
What also makes us a girl or a boy: sexual behaviour
Research released brain acquires ‘gender identity’ not for influence of sex hormones but instead from gene expression
Gees active before gonads even develop, week 2
