Sexual Differentiation and Determination Flashcards
What is sexual differentiation?
Process by which internal and external genitalia develop into female or male
What do sertoli cells produce?
produce anti-Mullerian Hormone
What do leydig cells produce?
produce testosterone
What is sexual determination?
Genetically controlled process dependant on the switch of the Y chromosome
Chromosomal determination of female or male
How is the SRY gene involved in gonadal development?
SRY gene is a transcription factor that transcribes itself alongisde a cascade of events = development of testes
In the absence of the SRY gene the ovaries develop
What are the two cells that the testis develop and what do they produce?
- Sertoli Cells = produce AMH
- Leydig Cells = produce testosterone
Describe gonadal development after fertilisation
After fertilisation a pair of gonads develop which are bipotential
Their precursor is derived from common somatic mesenchymal tissue precursors called genital ridge primordia on the posterior wall of lower thoracic lumbar region
Two ducts
- Mullerian (female)
- Wolffian (male)
These will develop into female/male internal genitalia depending on the hormones produced
Describe the three waves of cells that invade the genital ridge
1) PRIMORDIAL GERM CELLS
Become sperm (male) or oocytes (female)
2) PRIMITIVE SEX CORDS
Become sertoli cells (male) or granulosa cells (female)
3) MESONEPHRIC CELLS
Become blood vessels and Leydig cells (male) or Theca cells (female)
Describe primordial germ cell migration
Small cluster of cells in the epithelium of the yolk sac expand by mitosis at 3 weeks
They migrate to the connective tissue of the hind gut, to the region of the developing kidney and on to the genital ridge
Describe the formation of sex cords
- Cells from the germinal epithelium that overlies the genital ridge mesenchym migrate inwards as columns called the primitive sex cords
IN MALES
- SRY expression
- Sex cords will penetrate the medullary mesenchyme and surround PGCs to form testis cords
- Eventually become sertoli cells which express AMH
IN FEMALES
- There is no SRY expression
- Sex cords are ill-defined, do not penetrate as deeply instead condense in the cortex in small clusters around PCGs
- Become granulosa cells
Describe the role of mesonephric cells in gonadal development
- Originate in the mesonephric primordium lateral to the gential ridge
-
In males - act under the influence of pre-sertoli cells (which themselves express SRY) to form…
- Vascular tissue
- Leydig cells (synthesize testosterone, do not express SRY)
- Basement membrane – contributing to formation of seminiferous tubules and rete-testis
- In females without the influence of SRY they form…
- Vascular tissue
- Theca cells (synthesize androstenedione which is a substrate for estradiol production by the granulosa).
-
In males - act under the influence of pre-sertoli cells (which themselves express SRY) to form…
What is the role of theca cells?
Synthesise androstenedione which is a substrate for estradiol production by the granulosa
What are the two main structures involved in developing of internal reproductive organs?
Mullerian Duct
- Most important in female
- Inhibited in males by AMH
Wolffian Duct
- Most important in males, stimulated by testosterone
- Lack of stimulation by testosterone means regression in female
What is the role of 5-a-reductase?
- Testosterone is converted to 5-a-reductase to a more potent androgen called DHT (dihydrotestosterone)
- Occurs in the genital skin to form the male external genitalia
- DHT also binds to the testosterone receptor but is more potent
How does DHT cause differentiation of the male external genitalia?
- Clitoral area will enlarge into the penis
- Labia will fuse and become ruggated to form the scrotum
- The prostate forms
Why does DHT have no effect in females?
No substrate (testosterone) present in females so no effect
Provide a summary of sex differentiation from an undifferentiated gonad (male)
Males
- Y chromosome = SRY expression (transcription factor)
- SRY causes Sertoli cells to produce AMH which results in regression of the mullerian duct
- Sertoli cells cause leydig cells to be formed which produce testosterone
- Growth of the wolffian fuct to seminal vesicle and vas deferens
- Testosterone is converted to DHT by 5-a-reductase = growth of male external genitalia
Provide summary of sex differentiation from an undifferentiated gonad (female)
- No Y chromosome = No SRY
- No Sertoli cells but granulosa cells
- No AMH or testosterone
- Mullerian duct will grow into uterine tubes, uterus and vagina
- Absence of testosterone, wolffian duct will duct will regress
What is gonadal dysgenesis?
Sexual differentiation is incomplete e.g missing SRY or deletion of second X in females
e.g AIS, 5-a-reducatse deficiency, Turner Syndrome, Congenital Adrenal Hyperplasia
What is sex reversal?
Where the phenotype does not match the genotype e.g male genotypically but externally female
What is intersex?
Have components of both tracts or ambiguous genitalia. Sex of infant is difficult to determine
What is it called when testosterone is being made in an XY individual, but it has no effect?
AIS (androgen insensitivity syndrome)
The testes form and make AMH so the Mullerian duct regresses.
There is no differentiation of the Wolffian ducts, thus no external male genitalia
What is the difference between partial and complete AIS?
Complete AIS = appear female at birth despite being XY, but have undescended testes due to AMH
- Present with lack of body hair
- Diagnosed by ultrasound scan and male levels of androgen on karyotype
- Don’t respond to androgens so feel female
Partial AIS = Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris
What is the disorder called where an XY individual makes testosterone but no DHT?
- 5-a-reductase deficiency
- Testes form and make AMH so mullerian duct regresses
- The wolffian duct develops but there is no external genitalia due to inabillity to convert testosterone to 5-a-reductase in the genital skin
What can happen during puberty with 5-a-reductase deficiency?
Testosterone levels will increase during puberty and can induce virilisation
What is turner sydrome?
- XO have failure of ovarian function.
- · ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need 2 X’s for ovarian development.
- · Uterus and tubes are present but small, other defects in growth and development.
- · May be fertile…many have mosaicism.
- · Hormone support of bones and uterus
What happens when an XX female is exposed to high levels of androgens in-utero?
What does that result in?
Congenital adrenal hyperplasia is most common cause: 1:15,000.
- 21-OH deficiency means that progestogens are not converted into glucocorticoids and mineralocorticoids. If this enzyme is mutated it cant make cortisol.
- No cortisol means there is no negative feedback to the hypothalamus and anterior pituitary meaning there is excess production of CRH and ACTH.
- Excess ACTH will stimulate the rapid uptake of cholesterol into the adrenal cortex. The excess will be forced into androgen production due to 21-OH deficiency.
- Hence congenital adrenal hyperplasia
What are the features of CAH?
- Completeness of block varies
- Children may be assigned wrong gender at birth or may have ambiguos genitalia
- Possibility of ‘salt wasting’ due to lack of aldosterone, this can be lethal
- Need treatment with glucocorticoids to correct feedback
Explain the sexual differentiation process in an indvidual with congenital adrenal hyperplasia
XX female exposed to high levels of androgens in-utero due to 21-OH deficiency progestogens are not converted to glucocorticoids or mineralocorticoids, excess ACTH = stimulates rapid uptake of cholesterol and forced into androgen production
- No SRY, so no testes and no AMH
- Mullerian duct remains
Masculinised external genitalia but androgen levels not high enough to rescue Wolffian duct
