Sexual Differentiation

Question 1

At what weeks are bipotential?

Answer 1

<6 weeks: gonads
<7 weeks: internal genitalia
<8 weeks: external genitalia

Question 2

What determines internal and external sexual differentiation?

Answer 2

THE TESTIS. The ovary does not play a role. So an ovary or no gonad will result in female

Question 3

What is the bipotenital gonad?
Arises from?
Three parts?

Answer 3

-The genital ridge.
-intermediate mesoderm (important as defect in gonads can mean kidney defect)
-Ant-post
Pronephros ( caudal end froms adrenals)
Mesoneophros gonads and internal reproductive structures as well a Wolffian and Mullerian ducts)
Metanephros (kidneys)

Question 4

What 4 nuclear transcription factors involved in sexual differentiation?

What step in the process are all four involved?

What factors are involved with contributions of the yolk sac and endoderm?

What occurs in alteration of gene involved in this?

Answer 4

IGFR1; WT1; ST1; DAX1

formation of intermediate mesoderm to genital ridge

Germ cells migrate: C-Kit/Steel

If no bipotential gonad, no gonad, meaning external and internal female genitalia

Question 5

What is testicular differentitation determined by?

Answer 5

The SRY on the Y chromosome

Question 6

From a bipotential gonad, what genes are invloved in forming ovaries and testis?

Answer 6

Ovaries: FOXL2 with: DAX-1; RSPO1; WnT4 and Beta catenin (may inhibit male)
Testis: SRY to SOX-9 with: SF1 and FGF9

Question 7

What is the first cell that forms in the developing testis and what is important about this?

Answer 7

Sertoli cell

SRY gene found here, and is activated prior to sertoli cell development

Question 8

What is the role of SRY?

Answer 8

Stimulate SOX-9 (an autosomal gene)

Question 9

Process of getting SOX-9

Answer 9

• SF-1 initially transcribes SOX-9 and is up regulated by SRY
• Up regulates itself with positive feedback and stimulation of prostacyclin D and FGF9
• These inhibit ovarian transcription factors

Question 10

Function of prostacyclin D2 in SOX-9 expression?

Answer 10

Prostacylin D is formed by SOX-9 and recruits cells to a sertoli cell lineage in a paracrine manner (binding to nearby cells)

Question 11

Function of FGF9 in sexual determination?

Answer 11

Enhances proliferation (mitogen) of SF-1 cells, meaning and increased number of precursor SRY expressing cells and other gonadal cells.

Made by pre sertoli

Question 12

Loss of function critical in forming male gonads equals?

Answer 12

No gonads, female internal and external genitalia

Question 13

Primordial germ cell origin

If removed early what will they become?

Answer 13

Allantois (yolk sac) migrate to the genital ridge
Migrate using c-Kit/Steel
In testis they enter the cords
Go into ovaries, early meiosis then arrest

Follicles. Some factor in the testis that make them spermatogenic

Question 14

What will the Wolffian and Mullerian ducts form?

Answer 14

Wolffian (mesonephric): Internal male (epididymis, vas deferens, seminal vesicles)
Mullerian (paramesonephric): Are an invagination of the Wolffian ducts and form female internal genitalia (FT’s, uterus and upper vagina 1/3)

Question 15

Why must you need a testis to have male internal genitalia?

TF level

Answer 15

You need testosterone to maintain Wolffian structures, and AMH made by sertoli cells to regress Mullerian ones.
Note are paracrine

Leydig cell-(SF-1)- testosterone- androgen receptor - Wolffian duct stable
Sertoli cell -(SF-1)- AMH- AMH receptor- Mullerian duct regression

Question 16

Loss of function of AMH gene in male

Answer 16

Wolffian and Mullerian structures and often bilateral cyrptorchidism

Question 17

Loss of function in gene that synthesis testosterone or androgen receptor?

Answer 17

Has testis, but Wolffian duct has regressed.

Question 18

External Genitalia development

Answer 18

GENITAL TUBERCLE
Male: Will result if exposed to high levels of DHT
Lower concentrations of androgen or partial andorgen insensitivity will result in partial virlisation. Full insesnitivity will result in female external.

Question 19

What stimulates the production of leydig cells in utero as pituitary hasn’t developed?

Answer 19

Placental hCG in the first tri: stimulates leydig cells and through SF-1 and steroid genes produces testosterone
2nd and tri: Pituitary LH. Need this for fallace development

Need 5-alpha reductase to make DHT and form external genitalia

Question 20

External genitalia anatomically forming

Answer 20

Labioscrotal swellings: Labia majora and scrotum
Urethral folds: Labia minora and penis shaft
Glans: Clitoris or glans penis

Question 21

Loss of function of testosterone

Answer 21

Female external genitalia and Wolffian duct regression

Question 22

Loss or partial loss of 5-a reductase

Answer 22

Under virilised male genitalia (from complete female to hypospadias)
Then virilisation at puberty due to increased

Question 23

Clinical investigations at birth with ambiguous genitalia?

Answer 23

Karyotype and pelvic US. Presence of uterus = female genitalia = no AMH produced = no sertoli cell

Question 24

Virilised female

Answer 24

Female with XX and normal female internal genitalia: uterus.
Due to fetal exposure to androgens
Fetal: Congenital adrenal hyperplasia
Maternal: Severe PCOS or ingestion of male hormones

Question 25

Under virilised male

Answer 25

Testis, XY, normal male internal genitalia

Implies a lack or pre natal androgen exposure
e.g LH receptor mutation, androgen receptor mutation, Klinefelters