Sexual Differentiation: How to make a boy or a girl

Question 1

What are the 3 main events that determine sex?

Answer 1

Sex determination, during fertilisation: inheritance of X/Y from father.
Differentiation of gonads, week 5.
Differentiation of internal and external genital organs, after week 5.

Question 2

Outline the origin and differentiation of gonads

Answer 2

At week 2 primordial germ cells (PGCs) arise from the epiblast.
PGCs are pluripotent.
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.
At genital ridge: XX PGCs replicate at cortex; XY PGCs replicate at medulla.

Question 3

What does gonad gender decision rely on?

Answer 3

Genetic switches: general transcription factors - Wt1, Sf1
specific promoters of testis development - Sry, Sox9 specific promoters of ovarian development - Wnt-4, FoxL2.
Hormones

Question 4

What are the female PGCs?

Answer 4

oogonia (primary oocytes).
degenerates at sex cord cells producing granulosa (supports and provides nutrition to ovum).
cortex => layer of thecal cells => secrete androgens before those generated by the follicles.

Question 5

What are the male PGCs?

Answer 5

Male PGCs => spermatogonia
Sry influences definition + identity of Sertoli cells => secretion of AMH
AMH suppresses female development pathway
AMH induce cells in intermediate mesoderm to become leydig => secrete testosterone

Question 6

What is the origin and stages of kidney development?

Answer 6

Intermediate mesoderm (as the reproductive organs),
between the somites and lateral plate (each side of the aorta).
3 Stages: Pronephros - disappears soon after
Mesonephros - leaves remnants
Metanephros - becomes kidney
(mesonephros leaves behind ducts that become integral part of the reproductive system).

Question 7

When do internal genital organs begin to differentiate?

Answer 7

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

Question 8

How do internal genital organs form in females?

Answer 8

Müllerian duct kept due to absence of AMH.

becomes oviduct, uterus, cervix, upper part of vagina.

Question 9

How do internal genital organs form in males?

Answer 9

In male embryo: AMH causes Müllerian duct regression. testosterone promotes Wolffian duct differentiation.
Wolffian duct becomes epididymis, vas deferens, seminal vesicle.

Question 10

How do external genital organs develop?

Answer 10

At first embryos of both sexes show an elevated midline swelling – genital tubercle.
Tubercle consists:
- urethral groove (opening into urogenital sinus)
- paired urethral folds
- paired labioscrotal swellings

Question 11

How do external genital organs develop in males?

Answer 11

Some testosterone is converted into DHT.
DHT stimulates development of urethra, prostate and external genitals (scrotum and penis).
Genital tubercle => penis
Fusion of the urethral folds => spongy urethra
Labioscrotal swellings => scrotum

Question 12

How do external genital organs develop in females?

Answer 12

Absence of DHT
Genital tubercle => clitoris
Urethral folds remain open => labia minora
Labioscrotal swellings => labia majora
Urethral groove => vestibule

Question 13

What are the different types of abnormalities?

Answer 13

Chromosomal, hermaphroditism, gonadal dysfunction,

tract abnormalities, gonadal descent, external genitalia.

Question 14

Give an example of a chromosomal abnormality and its features?

Answer 14

Turner’s Syndrome:
Monosomy, XO
1:2500 females
99% non-viable embryos
Survivors fail to sexually mature at puberty
rudimentary ovaries, no menstruation, poor breast development.
Diagnosis confirmed through amniocentesis.

Question 15

What is a true hermaphrodite and its possible cause?

Answer 15

Extremely rare
Born with ovarian + testicular tissue (ovotestis)
46XX (SRY+), 45X (SRY+) and 45X.
Possible cause e.g. 2 ova fertilized by 2 sperm that fuse to form a tetragametic chimera.
External genitals may be ambiguous or appear female or male.

Question 16

What is a female pseudohermaphrodite
What is the appearance of the external genitals?
What are its features?
What is the possible causes?

Answer 16

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).

Question 17

What is a male pseudohermaphrodite? 
What is the appearance of the external genitals? 
What are its features?
How does it affect the testis?
What are the main causes?

Answer 17

46, XY with undervirilisation.
External genitals: incompletely formed, ambiguous or clearly female.
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).

Question 18

Which conditions are associated with male pseudohermaphroditism?

Answer 18

Androgen Insensitivity Syndrome (AIS) a.k.a. testicular feminisation. affects male births. (male) hormones are normal. dysfunctional 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.

Question 19

What is gonadal dysfunction?
What is it associated with?
What is the cause?
What is the external appearance?
How does it affect the testis?

Answer 19

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

Question 20

Give some examples of tract abnormalities

Answer 20

Uterine: e.g. unicornuate uterus
Vagina: e.g. agenesis
Ductus Deferens: unilateral or bilateral absence, failure of mesonephric duct to differentiate

Question 21

Give examples of conditions affecting gonadal descent

Answer 21

Cryptorchidism: affects males. may be unilateral/bilateral.
occurs 30% premature. descent may take place during year 1.
Undescended ovaries: quite rare. detected in clinical fertility assessment.

Question 22

What is the most common condition in males that affects the external genitalia and what is the outcome?

Answer 22

male hypospadia - failure of male urogenital folds to fuse.

outcome: proximally displaced urethral meatus.

Question 23

What determines if someone is a boy or a girl?

Answer 23

Sexual behaviour.
Research from mutants revealed that brain acquires ‘gender identity’ not from influence of sex hormones but from gene expression, given correlation between inactivation of genes from X chromosome + predisposition to transexualism.