Sexual Differentiation and Disorders Flashcards
What is sexual determination?
genetically controlled process
dependent on the SRY switch in Y chromosome
this determines whether development will be directed towards M/F
What is sexual differentiation?
process by which internal and external genitalia develop as M or F
What is the nature of sexual determination and differentiation?
BOTH contiguous processes
BOTH traverse several stages
What are the stages of sex differentiation?
- genotypic sex (XX or XY)
- gonadal sex (testis or ovaries)
- phenotypic sex (usually assessed by external genitalia at birth)
- legal sex
- gender identity
How does SRY gene dictate gonadal sex?
[In XY]
SRY gene expression = testis development
[in XX]
no SRY expression, ovaries develop
What is the SRY gene? What is its role?
= sex determining region Y (SRY)
present on Y chr
expression switched on briefly at >7weeks gestation
SRY = TF, which results in auto-activation of SRY gene and downstream cascades encouraging male pathway processes
makes gonad -> testis
What cell types does the testis develop? What hormones do they produce?
SERTOLI CELLS
anti-Mullerian hormone (AMH)
LEYDIG CELLS
testosterone
What is the nature of the undifferentiated gonad?
after fertilisation
gonads are BIPOTENTIAL
gonadal precursor (genital ridges) derived from COMMON SOMATIC MESENCHYMAL TISSUE
Where are the genital ridges primordia located?
[between 3.5-4.5wpc]
posterior wall of lower thoracic lumbar region
What is meant by undifferentiated gonads having BIPOTENTIALl?
have capacity to delelop into either M or F
via presence of both Mullerian and Wollfian ducts
What does the Mullerian duct become?
will develop into;
- uterus
- uterine tubes
- upper 1/3 of vagina
What will the Wolffian duct become?
will develop into:
- epididymis
- vas Deferens
- some aspects of prostate
What are the 3 waves of cells that invade the genital ridge?
PRIMORDIAL GERM CELLS
become sperm or oocytes
PRIMITIVE SEX CORDS become Sertoli (m) or Granulosa (F) cells
MESONEPHRIC CELLS
become blood vessels and Leydig (m) or Theca (f) cells
What are ‘primordial germ cells?’
- initially small cell cluster within yolk sac epithelium
- initially diploid so divide by mitosis
- migrate to connective tissue of hindgut
- specifically to the developing kidney and then to genital ridge (completed by 6wks)
What are the primitive sex cords?
Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns
What do the primitive sex cords become in males?
SERTOLI CELLS
- XY = SRY expression
- Penetrate the medullary mesenchyme & surround the PGCs to form testis cords.
- Eventually become Sertoli Cells which express Anti-mullerian hormone (AMH).
What do the primitive sex cords become in females?
GRANULOSA CELLS
- XX = No SRY expression
- Sex cords are ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around PGCs.
- Eventually become Granulosa Cells.
What are mesonephric cells?
originate from the mesonephric primordium (lateral to genital ridges)
MALES
act under influence of Sertoli precursors, forming:
- vascular tissue
- Leydig cells (Testosterone +ve, SRY -ve)
- basement membrane (maes seminiferous tubules and rete-testis)
FEMALES
without SRY expression, go onto form:
- vascular tissue
- theca cells (synthetic androstenedione = substrate for E2 production)
What is the determination cascade for MALE sex?
Primordial germ cells -> spermatozoa
Primitive sex cords -> Sertolic cells (SRY, AMH)
Mesonephric cells -> Leydig cells (testosterone)
What is the determination cascade for FEMALE sex?
Primordial germ cells -> oocytes
Primitive sex cords -> granulosa cells (E2)
Mesonephric cells -> theca cells (androstenedione)
What is the function of granulosa cells that surround the primordial germ cell cluster?
to protect the oocytes held within
What are the 2 main structures involved in internal reproductive organ formation?
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
How is dihydrotestosterone (DHT) produced?
testosterone converted to DHT
(by 5-a-reductase)
occurs in the genital skin
What is DHT?
produced by 5-a-reductase
binds to testosterone receptors at higher potency than testosterone
causes differentiation of male external genitalia:
- clitoral area -> penis
- labia fuse and become rugged -> scrotum
- prostate forms
What happens if there is no DHT available?
female genitalia (external) are formed
e.g. in females, there is 5aRED but no testosterone so DHT cannot be made
What is the link between 5-a-reducatse and baldness?
5-a-reductase expressed in scalp
inhibits hair follicles
leads to male-pattern baldness
What is gonadal dysgenesis?
incomplete sexual differentiation
usually due to missing SRY expression in males
OR
partial or incomplete deletion of 2nd X chromosome in females
can also be used to describe general abnormal gonadal development
What is sex reversal?
phenotype DOES NOT MATCH genotype
What is intersex?
have some components of both Mullerian/Wolffian tracts or have ambiguous genitalia
difficult to determine sex of infant
usually prefer to be called disorder of sexual differentiation (DSD)
What is androgen insensitivity syndrome?
XY individual
testosterone is produced but has no effect
e.g. issue with testosterone receptor or the downstream cascade
RESULT: regression of wolffian ducts (no internal male genitalia)
still have DHT but no wolffian ducts so no external male genitalia
What is COMPLETE AIS?
AIS = androgen insensitivity syndrome
incidence 1:20,000
appear completely female at birth (therefore assigned female gender, even though XY)
have undescended testes
How is complete AIS usually diagnosed?
AIS = androgen insensitivity syndrome
- primary amenorrhoea
- no body hair
USS and karyotype analysis
male level of androgens
never responded to androgen so will often feel female
What is PARTIAL AIS?
AIS = androgen insensitivity syndrome
incidence unknown as most likely a spectrum
varying degrees of penile and scrotal development or ambiguous genitalia to large clitoris
surgery used to be universal but now considered optional
decisions made on potential - so can be difficult for parents
What happens with 5-a-reducatase deficiency?
XY individual
testosterone made but no DHT as no 5-a-reductase or deficiency
this is autosomal recessive (therefore higher incidence in consanguineous marriage)
incidence varies
testes form, AMH acts, testosterone acts
internal structures form
external structures do not develop
may appear mainly female or have ambiguous genitalia
degree of deficiency informs on presentation
AT PUBERTY
need to re-assess
high [testosterone] at adrenarche may induce virilisation
What is Turner’s syndrome?
X- (lacks complete 2nd X chr)
incidence 1:3000
causes failure of ovarian function
‘streak’ ovaries (ovarian dysgenesis)
uterus and tubes are small but present
also other defects in growth and development
may be fertile
many have mosaicism
hormone support of bones and uterus
What is congenital adrenal hyperplasia?
(CAH)
most common cause of gonadal dysgenesis
incidence 1:15,000
XX individual
exposed to high levels of androgens in utero
completeness of block varies
most commonly 21alpha hydroxylase
then 17-alpha-hydroxylase or 11-beta hydroxylase
can be wrongly assigned at birth or have ambiguous genitalia
Salt-wasting crisis: due to lack of aldosterone (can be lethal)
RX: glucorticoids to correct feedback loop
