Lecture 19: Sex determination, differentiation and development Flashcards
Define sex determination;
Commitment of the indifferent gonad to a testis or an ovary
Define sex differentiation;
The phenotypic development of genital structures due to the action of hormones produced following gonadal development
In mammals what is sex determination controlled by?
Genetics
22 autosomes
1 pair of sex chromosomes
F (XX) (Oocytes = X always)
M (XY) (two populations of spermatozoa)
Describe the flow chart of sex determination;
Sex Chromosomes
Gonads
Hormones
= Internal ducts and external genitalia
Hormones and external genitalia determines gender which is a social construct.
Describe sex determination programming;
Genetically programmed in a critically TIMED and gene DOSAGE dependent manner
How have we come to understand sex determination;
- Knockout mice
- Identifying specific chromosomal and gene defects in patients with abnormalities of of sexual phenotype
Describe various chromosome combinations;
XO = turners syndrome XXX(X) = female, retarded XX(X)Y = Klinefelters syndrome XYY = Antisocial tall male XX(X)YY = Multiple abnormalities, mentally retarded
Whats an observation from chromosome abnormalities?
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
What is the sex determination factor?
Y chromosome contains a dominant gene that initiates the male pathway by directing testis formation in the embryonic gonad
(without this femaleness occurs naturally)
Describe testis development (overview)
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)
What is the testis determination factor?
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
Describe the flow chart for male sex determination and differentiation
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
Describe the flow chart for female sex determination and differentiation
Mesoderm -> Bipotential gonad -> Ovary -> Oestrogens and progestagens
Mullerian duct development -> Internal female genitals
Wolfian duct regression
What is notable of the sex determination and differentiation flow chart
AMH and testosterones have action on cells, while estrogen and prostagens dont. i.e female differentation is not under hormonal control
Describe the molecular sex determination;
Mesoderm -(WT-1, LIM-1, SF1) -> Bipotential gonad -(DAX-1)-> Ovary
Mesoderm -(WT-1, LIM-1, SF1) -> Bipotential gonad -(SRY, DMRT1,2, SOX9)-> Testis
What causes sex differentiation;
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
Describe the primitive gonad week 3;
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)
Describe the primitive gonad weeks 4-5;
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)
When does testicular differentiation occur and what happens?
Week 6 and sortoli + leydig cells are formed
Describe sortoli cell formation in week 6;
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)
What do the sertoli cells secrete in the primitive gonad;
AMH, which causes mullerian duct regression
Describe leydig cell formation in week 6
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
When does ovarian differentiation occur?
Week 9
Describe ovarian differentiation in week 9;
Differentiation requires no active intervention
Commitment to ovarian differentiation occurs week 9 although follicles are not seen until week 13
Describe cell migration and ovarian formation in week 9;
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
What is the abisexual stage;
When both wolffian (Male) and mullerian (female) ducts are present (until week 8 of development)
In male differentiation when do the mulleriance ducts regress?
Mullerian ducts start to regress in response to sertoli AMH at week 8 and are absent by week 10.
Describe how male internal genitalia is formed;
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.`
Summerise testicular differentiation;
- Ongoing development of the seminiferous tubules
- Degeneration of the mullerian duct
- Persistance of the wolffian ducts
Describe the last step in testicular differentiation;
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
In ovarian differentiation when does wolffian duct regression start?
10 weeks
Describe ovarian differentiation;
- 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
Describe sex differentiation of the urogenital sinus for females;
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
Describe sex differentiation of the urogenital sinus for males;
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
Describe male and female external gential development;
The male and female external genitaloa develop from a single bipotential precursor
Describe differentiation of the male external genitalia;
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.
Describe differentiation of the female external genitalia;
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.
What is pseudohermaphroditism;
When gonads agree with chromosome sex but external objects are of the opposite sex.
Describe female pseudohermaphroditism;
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)
Describe male pseudohermaphroditism;
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
What is androgen resistance syndrome;
Due to absence of androgen receptors
gonads are testis
but genital ducts and/or external genitals are incompletely masculinised
