11. Sexual Differentiation: how to make a boy or a girl Flashcards
What main events make a boy/girl?
What makes a boy/girl takes involves 3 main events
(1) Sex determination, during fertilization
(2) Differentiation of gonads, week 5
(3) Differentiation of internal and external genital organs, after week 5
Prevalence of genital abnormalities: 1 in 4500
Sex determination
Sex is determined at fertilisation
Inheritance of X/Y from father
Gonad origin and differentiation
At week 2 primordial germ cells (PGCs) arise from the epiblast
PGCs are pluripotent
What do the PGCs do?
PGC’ migrate to yolk sac stalk to avoid becoming imprinted
Later return, travelling to the genital ridge (next to kidney) and become the indifferent gonad
What happens at the genital ridge?
At genital ridge: XX PGCs replicate at cortex; XY PGCs replicate at the medulla
Gonad gender decision relies on:
Gonad gender decision relies on:
- Genetic switches - Hormones
Genetic switches:
general transcription factors,
e.g. Wt1, Sf1
- specific promoters of testis development
e.g. Sry, Sox9
specific promoters of ovarian development
e.g. Wnt-4, FoxL2
General transcription factors
Wt1, Sf1
Specific promoters of testis development
Sry, Sox9
Specific promoters of ovarian development
Wnt-4, FoxL2
Overview of gonad cell line fates
urogenital ridge -> bipotential gonad -> future ovary or future testis
Female gonad cell line fate
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
Male gonad cell lines
Male PGCs => spermatogonia
Sry influences definition + identity of Sertoli cells => secretion of AMH (Anti-Müllerian Hormone)
AMH supresses female development pathway
AMH induce cells in intermediate mesoderm to become leydig => secrete testosterone
Kidney development
Origin: intermediate mesoderm (as the reproductive organs)
Where: between the somites and lateral plate (each side of the aorta)
3 Stages:
Pronephros - disappears soon after
- Mesonephros - leaves remnants
- 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:
- paramesonephric a.k.a. Müllerian
- mesonephric a.k.a. Wolffian
Internal genital organ fate in female embryos
In female embryo: Müllerian duct is kept due to the absence of AMH
Müllerian duct => oviduct
uterus
cervix
upper part of the vagina
Internal genital organ fate in male embryos
In male embryo:
- AMH causes Müllerian 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 in males
Some testosterone is converted into dihydrotestosterone (DHT)
DHT stimulates development of the urethra, prostate and external genitals (scrotum and penis)
Genital tubercle => penis
Fusion of the urethral folds => spongy urethra
Labioscrotal swellings => scrotum
External genital organs in females
Absence of DHT Genital tubercle => clitoris Urethral folds remain open => labia minora Labioscrotal swellings => labia majora Urethral groove => vestibule
Abnormalities
Chromosomal Hermaphroditism Gonadal dysfunction Tract abnormalities Gonadal descent External genitalia
Turner’s syndrome
Chromosomal
Monosomy, XO
1:2500 females (does not affect males)
99% non-viable embryos
Survivors fail to sexually mature at puberty
Exhibit several physical abnormalities (next slide)
Diagnosis confirmed through amniocentesis
Klinefelter’s syndrome
Chromosomal
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. gynecomastia)
Diagnosis confirmed through amniocentesis
Hermaphroditism
Named after the offspring of the Greek gods Hermes and Aphrodite
True hermaphrodite
Female pseudohermaphrodite
Male pseudohermaphrodite
(note: these colloquial terms are used for your understanding only and not actually used in the medical profession)
True hermaphrodites
Extremely rare
Born with both ovarian and testicular tissue (ovotestis)
46XX (SRY+), 45X (SRY+) and 45X
Possible cause e.g. two ova fertilized 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 virilization (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 virilizing adrenal hyperplasia)
Male pseudohermaphrodite
46, XY with undervirilization
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)
Androgen insensitivity syndrome
A.k.a. testicular feminization
Affects 1:20000-64000 male births
(Male) hormones are normal
Disfunctional receptor to these hormones
Leydig cell hypoplasia
Leydig cells do not secrete testosterone
Possible reason: body insensitive to LH
External genitalia normally female/slightly ambiguous
No female internal genitalia
(uterus) develops
Gonadal dysfunction
e.g. XY gonadal dysgenesis, a.k.a. 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
Tract abnormalities
Some examples:
Uterine: e.g. unicornuate uterus
Vagina: e.g. agenesis
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
The 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 boy or girl: sexual behaviour
Research from mutants revealed that the brain acquires its ‘gender identity’ not from the influence of sex hormones…
… but instead from gene expression, given the correlation between inactivation of genes from the X chromosome and predisposition to transexualism
In mouse embryos, 51 genes are expressed differently between male and female brain prior to advent of sex hormones (RT-PCR)
These genes are active before gonads even develop, let along differentiate, about week 2 of development
Money, J: ‘Gender identity is one’s own categorization of one’s individuality… as experienced in self awareness of one’s own mental processes and own’s actual behaviour’
This breakthrough can potentially help surgeons to decide which gender to opt in cases of genital malformation or of transexualism
