Lecture 19: Sex determination, differentiation and development

Question 1

Define sex determination;

Answer 1

Commitment of the indifferent gonad to a testis or an ovary

Question 2

Define sex differentiation;

Answer 2

The phenotypic development of genital structures due to the action of hormones produced following gonadal development

Question 3

In mammals what is sex determination controlled by?

Answer 3

Genetics
22 autosomes
1 pair of sex chromosomes

F (XX) (Oocytes = X always)
M (XY) (two populations of spermatozoa)

Question 4

Describe the flow chart of sex determination;

Answer 4

Sex Chromosomes
Gonads
Hormones
= Internal ducts and external genitalia

Hormones and external genitalia determines gender which is a social construct.

Question 5

Describe sex determination programming;

Answer 5

Genetically programmed in a critically TIMED and gene DOSAGE dependent manner

Question 6

How have we come to understand sex determination;

Answer 6

• Knockout mice

- Identifying specific chromosomal and gene defects in patients with abnormalities of of sexual phenotype

Question 7

Describe various chromosome combinations;

Answer 7

XO = turners syndrome
XXX(X) = female, retarded
XX(X)Y = Klinefelters syndrome
XYY = Antisocial tall male
XX(X)YY = Multiple abnormalities, mentally retarded

Question 8

Whats an observation from chromosome abnormalities?

Answer 8

The number of chromosomes does not affect the primary determination of gonadal sex

i.e if Y is present at all it will be male, regardless of n.x

Question 9

What is the sex determination factor?

Answer 9

Y chromosome contains a dominant gene that initiates the male pathway by directing testis formation in the embryonic gonad

(without this femaleness occurs naturally)

Question 10

Describe testis development (overview)

Answer 10

Testis development in response to testicular hormones (sex determination factor??) which determine the sexual fate of the embryo, against the basic feminine trend (this would occur if it werent for testicular hormones)

Question 11

What is the testis determination factor?

Answer 11

SRY; Sex determining region on the Y chromosome.

• Expression patterns in gondal ridge at proper times of development
• Can be found in XX males but not in XY Females
• Injection of transgene into mouse XX embryo causes testicular development

Question 12

Describe the flow chart for male sex determination and differentiation

Answer 12

Mesoderm -> Bipotential gonad -(SRY)-> Testis -> Sertoli cells and Leydig cells

Sertoli cells -> antimullerian hormone (AMH) -> Mullerian duct regression

Leydig cells -> Testosterone -> Wolffian duct development -> Internal male genitalia

Question 13

Describe the flow chart for female sex determination and differentiation

Answer 13

Mesoderm -> Bipotential gonad -> Ovary -> Oestrogens and progestagens

Mullerian duct development -> Internal female genitals

Wolfian duct regression

Question 14

What is notable of the sex determination and differentiation flow chart

Answer 14

AMH and testosterones have action on cells, while estrogen and prostagens dont. i.e female differentation is not under hormonal control

Question 15

Describe the molecular sex determination;

Answer 15

Mesoderm -(WT-1, LIM-1, SF1) -> Bipotential gonad -(DAX-1)-> Ovary

Mesoderm -(WT-1, LIM-1, SF1) -> Bipotential gonad -(SRY, DMRT1,2, SOX9)-> Testis

Question 16

What causes sex differentiation;

Answer 16

The phenotypic development of genital structures due to the actions of hormones produced following gonadal development (only gonad dependent for males, as without an ovary, females development will still occur)

Early on female and male gonads are indifferent and cant be discriminated

Question 17

Describe the primitive gonad week 3;

Answer 17

Gonads are derived from two distinct tissues;

• Germ cells (originate outside the embryo and migrate to the genital ridge and colonise the matrix to form the gametes)
• Mesoderm (forms the genital ridge which gives rise to the gonad matrix)

Question 18

Describe the primitive gonad weeks 4-5;

Answer 18

The genital ridge develops at ~32 days as a thicking of the coelmic epithelium

Close anatomical and developmental association with the renal system (wolffian ducts or mesonephric)

Question 19

When does testicular differentiation occur and what happens?

Answer 19

Week 6 and sortoli + leydig cells are formed

Question 20

Describe sortoli cell formation in week 6;

Answer 20

In response to SRY signals, interstitial cells in the gonadal ridge differentiate into sertoli cells

Germ cells aggregate with sertoli cells, become enclosed and form seminiferous cords and later tubules (germ cells differentiate as pro-spermatogonia)

Question 21

What do the sertoli cells secrete in the primitive gonad;

Answer 21

AMH, which causes mullerian duct regression

Question 22

Describe leydig cell formation in week 6

Answer 22

Between the cords, stromal tissue develop into interstitial glands of leydig.

Secretes testosterone which causes;

• differentiation and growth of wolffian duct structures
• When converted to 5A DHT, the masculinisation of the external genitalia

Question 23

When does ovarian differentiation occur?

Answer 23

Week 9

Question 24

Describe ovarian differentiation in week 9;

Answer 24

Differentiation requires no active intervention

Commitment to ovarian differentiation occurs week 9 although follicles are not seen until week 13

Question 25

Describe cell migration and ovarian formation in week 9;

Answer 25

In the absence of SRY signal, germ cells migrating into the primordial gonad differentiation into oogonia and cause mesenchymal cells to differentiate as granulosa cells thus forming primordial follicles

Question 26

What is the abisexual stage;

Answer 26

When both wolffian (Male) and mullerian (female) ducts are present (until week 8 of development)

Question 27

In male differentiation when do the mulleriance ducts regress?

Answer 27

Mullerian ducts start to regress in response to sertoli AMH at week 8 and are absent by week 10.

Question 28

Describe how male internal genitalia is formed;

Answer 28

In response to testosterone wolffian ducts integrate into the genital system, with their subsequent development into the epididymis, vas deferns and seminal vesicles

Testosterone actively maintains wolffian ducts, if these androgens stop then wolffian developments stops and regresses.

Testicular hormones prevent the spontaneous development of female genitalia.`

Question 29

Summerise testicular differentiation;

Answer 29

• Ongoing development of the seminiferous tubules
• Degeneration of the mullerian duct
• Persistance of the wolffian ducts

Question 30

Describe the last step in testicular differentiation;

Answer 30

Testicular descent;
- Testis descend from initial para-renal position to the scrotum (several phases) controlled by mechanical and endocrine factors

Passage of the testis through the inguanal canal doesnt normally occur until the 7th month

Question 31

In ovarian differentiation when does wolffian duct regression start?

Answer 31

10 weeks

Question 32

Describe ovarian differentiation;

Answer 32

• Mullerian ducts persist and develop to give rise to the oviducts, uterus, cervix, and possibly upper vagina

If gonads are removed in female fetus this still occurs!

If exposed to any androgens then female fetuses develop male internal genitalia

Question 33

Describe sex differentiation of the urogenital sinus for females;

Answer 33

Female differentiation;

• Characterised by the formation of the vagina
• At 15 weeks the mullerian and wolffian structures fuse to from a vaginal plate and aquire a lumen
• Down growth of the vagina plate leads to a seperate opening on the perineum

Question 34

Describe sex differentiation of the urogenital sinus for males;

Answer 34

Male differentiation;
- Conversion of testosterone to 5a DHT by 5a reductase accounts for the development of the urogenital sinus, characterised by prostatic development and the repression of vaginal development

Question 35

Describe male and female external gential development;

Answer 35

The male and female external genitaloa develop from a single bipotential precursor

Question 36

Describe differentiation of the male external genitalia;

Answer 36

Male differentiation;

• Masculinisations of the external genitalia organs begins in the 10 week old fetus by lengthening of the anogenital distance
• Fusion of the labioscrotal (urethral) fold to enclose the urethral tube, forming the shaft of the penis
• Genital swellings become the scrotal swellings, and fuse in the midline, forming the scrotum
• The genital tubercle expand to form the glans penis.

Question 37

Describe differentiation of the female external genitalia;

Answer 37

Female differentiation;

• The urethral folds and genital swellings remain seperate forming the labia majora and minora
• The genital tubercle forms the clitoris
• If the ovary is removed these changes still occur, indicating their independence of ovarian endocrine activity.

Question 38

What is pseudohermaphroditism;

Answer 38

When gonads agree with chromosome sex but external objects are of the opposite sex.

Question 39

Describe female pseudohermaphroditism;

Answer 39

46 XX DSD

• Ovarian and mullerian ducts are normal
• external genitalia are abnormal and masculinised if exposed to androgens

i. e
- Congenital adrenal hyperplasia
- Adrenogenital syndrome
- Steroid aromatase deficiency
- CYP21 (21 hydroxylase)

Question 40

Describe male pseudohermaphroditism;

Answer 40

Gonads are testes, but the genital ducts and or external genitals are incompletely masculinised.

Defects of androgen-dependant target tissue

• 5a Reductase 2 deficiency
• Androgen resistance

Question 41

What is androgen resistance syndrome;

Answer 41

Due to absence of androgen receptors

gonads are testis
but genital ducts and/or external genitals are incompletely masculinised