Sexual differentiation and disorders Flashcards
1
Q
What is sexual determination?
A
- genetically controlled process dependent on the SRY gene on the Y chromosome
- chromosomal determination of male or female
2
Q
What is sexual differentiation?
A
- The process by which internal and external genitalia develop as male or female
- The type of gonads that develop determine what internal and then external genitalia we have
3
Q
What are the several stages of sexual differentiation?
A
- Genotypic sex - XX or XY
- Gonadal sex - XY testes and XX ovaries
- Phenotypic sex - internal and external genitalia (usually same as gonadal sex, but not always)
- Legal sex - whats on birth certificate
- Gender identity - what you yourself feels is appropriate
4
Q
What determines the gonadal sex?
A
- SRY (sex determining region Y) gene creates the testis
- SRY switches on briefly during embryo development (> week 7) to make the gonad into a testis - in its absence, and ovary is formed
5
Q
How does the SRY gene work?
A
- Codes for a transcription factor
- Binds upstream of DNA causing the gene to be read
- Can also bind to the area itself and cause more of itself to be produced (amplification)
6
Q
What are the two important cells that testis develop?
A
- Sertoli cells produce anti-Mullerian hormone (AMH)
- Leydig cells make testosterone
- These products influence further gonadal and phenotypic sexual development
7
Q
How does gonadal development occur?
A
- after fertilisation, bipotential gonads develop
- their precursor is derived from genital ridge primordia (somatic mesenchymal tissue precursors) on posterior wall of lower thoracic lumbar region
- Wolffian duct will develop into male internal genitalia (VD, seminal vesicles, prostate)
- Mullerian duct will develop into female
- We have both ducts at this stage so any embryo can develop into either sex
- Dependent on SRY the genital ridge will form ovaries or testes
8
Q
What are the 3 waves of cells that invade the genital ridge?
A
- Primordial germ cells - become sperm or oocytes. Migrate from the germ sac
- Primitive sex cords - become Sertoli or Granulosa cells
- Mesonephric cells - become blood vessels and Leydig or Theca cells - make androgens
9
Q
How do primordial germ cells migrate to the genital ridge?
A
- An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis around 3 weeks
- They then migrate to the connective tissue of the hind gut, to the region of the developing kidney and on to the genital ridge - completed by 6 weeks
10
Q
How do the primitive sex cords get to the genital ridge?
A
- Surround the gametes
- Males = migrate in a tubular way
- Females = surround them in clumps - males ovarian
11
Q
How are the sertoli cells/ granulosa made?
A
Males:
- SRY expression
- penetrate the medullary mesenchyme and surround the PGCs to form testis cords
- eventually become Sertoli cells which express AMH
Females
- No SRY expression
- Sex cords are ill defined and don’t condense in the cortex as small clusters around PGCs
- Eventually become Granulosa cells
12
Q
What do the mesonephric cells become?
A
- Originate in the mesonephric primordium, just lateral to genital ridges
- Males - act under influence of pre-sertoli cells (which express SRY) to form vascular tissue, leydig cells (synthesise testosterone), and basement membrane - contributing to formation of seminiferous tubules and rete-testis
- Females - no influence of SRY, they form vascular tissue and Theca cells (synthesise androstenedione, a substrate for oestrogen production by granulosa)
13
Q
Gonadal sex summary
A
Males
- PGCs –> spermatozoa
- Primitive sex cords –> Sertoli cells (express SRY, secrete AMH)
- Mesonephric cells –> Leydig cells (secrete testosterone)
Females
- PGCs –> Oocytes
- Primitive sex cords –> Granulosa cells (oestradiol)
- Mesonephric cells –> Theca cells (andronstenediol)
14
Q
What are the 2 main structures involved in the formation of internal reproductive organs?
A
- Mullerian ducts - female, inhibited by AMH in males
- Wolffian ducs - male, stimulated by testosterone. A lack of stimulation by testosterone causes regression
15
Q
How does 5-alpha-reductase cause external differentiation?
A
- Testosterone is converted in the genial skin to the more potent androgen DHT by 5-a-reductase
- DHT binds to the testosterone receptor, but is 10x more potent
- DHT causes differentiation of the male external genitalia
- In the absence of DHT, the female external genitalia form - female still has 5-a-reductase, but no DHT
16
Q
What does DHT cause in the male?
A
- Differentiation of external genitalia
- Clitoral area enlarges into penis
- Labia fuse and become rugated to form scrote
- Prostate forms
- Urethral fold enlarges, folds over on itself and makes a tube
17
Q
What external differentiation occurs in females?
A
- No DHT so the genital tubercle swells slightly and becomes the clitoris
- Urethral folds become the labia majora and minora.
18
Q
Sex differentiation summary males
A
XY
- SRY gene causes differentiation into testes
- Sertoli cells produce AMH, which causes regression of mullerian ducts
- Leydig cells produce testosterone, whih causes differentiaation and growth of Wolffian duct structures, seminal vesicles and VD
- Testosterone is converted into DHT (10x more potent than testosterone) by 5-alpha reductase.
- DHT causes external genitalia differentiation - fusion of labia to scrotal folds growth of phallus and prostate
19
Q
Sex differentiation summary females
A
- XX
- absence of SRY causes differentiation into ovary
- Mullerian ducts differentiate and grow into uterine tubs, uterus and upper 1/3 of vagina
- Lack of testosterone leads to vagina, labia and clitoris
- Regression of Wolffian ducts
20
Q
What are the 3 main disorders of sexual differentiation?
A
- Gonadal dysgenesis - Sexual differentiation is incomplete. Usually missing SRY in males or partial/complete deletion of second X in female. Also used as a general description of abnormal development of the gonads.
- sex reversal - phenotype doesnt match genotype, e.g. may have male genotype but female external genitalia
- Intersex - have some components of both tracts or ambiguous genitalia - difficult to determine sex of an infant
21
Q
What causes androgen insensitivity syndrome (AIS)?
A
- Testosterone receptor not working (mutation of receptor or its secondary messenger system)
- There is AMH so no mullerian ducts
- There is DHT being made, but no effect - so female external genitalia
22
Q
What are the symptoms of complete AIS?
A
- appear completely female at birth and assigned female gender despite XY
- have undescended testes
- usually present with primary amenorrhoea
- lack of body hair is a clue
- US scan and karyotype with male levels of androgens
- Never responded to androgen so appear and feel female
23
Q
What are the symptoms of partial AIS?
A
- Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris
- Surgery was universal, but now optional or at least delayed
- Decisions made on potential, very difficult for parents
24
Q
What happens in 5-alpha-reductase deficiency?
A
- XY - SRY gene present
- testes form, AMH and testosterone act
- Internal structures form, but not external
- May appear female or have ambiguous genitalia
- The degree of enzyme block varies, and so does the presentation therefore
25
Q
What is Turner syndrome?
A
- 45X0
- Failure of ovarian function
- “Streak” ovaries = ovarian dysgenesis - illustrates that we need 2Xs for ovarian development
- Uterus and tubes are present but small, other defects in growth and development
- may be fertile, may have mosaicism
- hormones support of bone and uterus
26
Q
What causes congenital adrenal hyperplasia?
A
- 21-hydroxylase defect - cannot make cortisol
- make lots of progestagens - can only then make androgens from there
- Lack of cortisol - want to make more progestagens, giving more and more androgens
27
Q
What are the symptoms of CAH?
A
- have both mullerian and wolffian ducts - so both female and male internal genitalia
- male external genitalia as have lots of Testosterone and so DHT
- Completeness of the block varies
- If enzyme is absent, then child may be wrongly gender assigned at birth, or have ambiguous genitalia
- Also in CAH, need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal
- need glucocorticoid treatment to correct feedback
28
Q
What is the basic process of steroidogenesis?
A
- All have 3 6C rings, then a 5C ring with a C tail
- Cholesterol is the precursor for all steroids
- Taken into cells, long chain is clipped using side-chain cleavage enzyme
- If 22-27 are clipped = prostagens
- Only difference between steroids is the positioning of OHs etc
- Clip off 2 more from side chain - all androgens
- Clip another 1 off - all oestrogens
29
Q
What is the hypothalamic pituitary adrenal axis?
A
- Increased CRH causes pituitary to secrete ACTH
- ACTH stimulates rapid cholesterol uptake into the adrenal cortex
- Upregulates cholesterol side-chain cleavage enzyme
- Increases glucocorticoid (cortisol) secretion
- Negative feedback of cortisol on pituitary and hypothalamus
30
Q
What happens to the HPA axis in CAH?
A
- Cortisol itself doesnt rise because of enzyme block
- No negative feedback > increase in CRH and ACTH - make more and more steroids, accumulating as androgens.
