Sexual Differentiation Flashcards
At what weeks are bipotential?
<6 weeks: gonads
<7 weeks: internal genitalia
<8 weeks: external genitalia
What determines internal and external sexual differentiation?
THE TESTIS. The ovary does not play a role. So an ovary or no gonad will result in female
What is the bipotenital gonad?
Arises from?
Three parts?
-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)
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?
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
What is testicular differentitation determined by?
The SRY on the Y chromosome
From a bipotential gonad, what genes are invloved in forming ovaries and testis?
Ovaries: FOXL2 with: DAX-1; RSPO1; WnT4 and Beta catenin (may inhibit male)
Testis: SRY to SOX-9 with: SF1 and FGF9
What is the first cell that forms in the developing testis and what is important about this?
Sertoli cell
SRY gene found here, and is activated prior to sertoli cell development
What is the role of SRY?
Stimulate SOX-9 (an autosomal gene)
Process of getting SOX-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
Function of prostacyclin D2 in SOX-9 expression?
Prostacylin D is formed by SOX-9 and recruits cells to a sertoli cell lineage in a paracrine manner (binding to nearby cells)
Function of FGF9 in sexual determination?
Enhances proliferation (mitogen) of SF-1 cells, meaning and increased number of precursor SRY expressing cells and other gonadal cells.
Made by pre sertoli
Loss of function critical in forming male gonads equals?
No gonads, female internal and external genitalia
Primordial germ cell origin
If removed early what will they become?
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
What will the Wolffian and Mullerian ducts form?
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)
Why must you need a testis to have male internal genitalia?
TF level
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
Loss of function of AMH gene in male
Wolffian and Mullerian structures and often bilateral cyrptorchidism
Loss of function in gene that synthesis testosterone or androgen receptor?
Has testis, but Wolffian duct has regressed.
External Genitalia development
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.
What stimulates the production of leydig cells in utero as pituitary hasn’t developed?
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
External genitalia anatomically forming
Labioscrotal swellings: Labia majora and scrotum
Urethral folds: Labia minora and penis shaft
Glans: Clitoris or glans penis
Loss of function of testosterone
Female external genitalia and Wolffian duct regression
Loss or partial loss of 5-a reductase
Under virilised male genitalia (from complete female to hypospadias)
Then virilisation at puberty due to increased
Clinical investigations at birth with ambiguous genitalia?
Karyotype and pelvic US. Presence of uterus = female genitalia = no AMH produced = no sertoli cell
Virilised female
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
Under virilised male
Testis, XY, normal male internal genitalia
Implies a lack or pre natal androgen exposure
e.g LH receptor mutation, androgen receptor mutation, Klinefelters
