Sexual Differentiation and Disorders

Question 1

What is sexual determination?

Answer 1

genetically controlled process
dependent on the SRY switch in Y chromosome
this determines whether development will be directed towards M/F

Question 2

What is sexual differentiation?

Answer 2

process by which internal and external genitalia develop as M or F

Question 3

What is the nature of sexual determination and differentiation?

Answer 3

BOTH contiguous processes

BOTH traverse several stages

Question 4

What are the stages of sex differentiation?

Answer 4

• genotypic sex (XX or XY)
• gonadal sex (testis or ovaries)
• phenotypic sex (usually assessed by external genitalia at birth)
• legal sex
• gender identity

Question 5

How does SRY gene dictate gonadal sex?

Answer 5

[In XY]
SRY gene expression = testis development

[in XX]
no SRY expression, ovaries develop

Question 6

What is the SRY gene? What is its role?

Answer 6

= 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

Question 7

What cell types does the testis develop? What hormones do they produce?

Answer 7

SERTOLI CELLS
anti-Mullerian hormone (AMH)

LEYDIG CELLS
testosterone

Question 8

What is the nature of the undifferentiated gonad?

Answer 8

after fertilisation

gonads are BIPOTENTIAL

gonadal precursor (genital ridges) derived from COMMON SOMATIC MESENCHYMAL TISSUE

Question 9

Where are the genital ridges primordia located?

Answer 9

[between 3.5-4.5wpc]

posterior wall of lower thoracic lumbar region

Question 10

What is meant by undifferentiated gonads having BIPOTENTIALl?

Answer 10

have capacity to delelop into either M or F

via presence of both Mullerian and Wollfian ducts

Question 11

What does the Mullerian duct become?

Answer 11

will develop into;

• uterus
• uterine tubes
• upper 1/3 of vagina

Question 12

What will the Wolffian duct become?

Answer 12

will develop into:

• epididymis
• vas Deferens
• some aspects of prostate

Question 13

What are the 3 waves of cells that invade the genital ridge?

Answer 13

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

Question 14

What are ‘primordial germ cells?’

Answer 14

• 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)

Question 15

What are the primitive sex cords?

Answer 15

Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns

Question 16

What do the primitive sex cords become in males?

Answer 16

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).

Question 17

What do the primitive sex cords become in females?

Answer 17

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.

Question 18

What are mesonephric cells?

Answer 18

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)

Question 19

What is the determination cascade for MALE sex?

Answer 19

Primordial germ cells -> spermatozoa

Primitive sex cords -> Sertolic cells (SRY, AMH)

Mesonephric cells -> Leydig cells (testosterone)

Question 20

What is the determination cascade for FEMALE sex?

Answer 20

Primordial germ cells -> oocytes

Primitive sex cords -> granulosa cells (E2)

Mesonephric cells -> theca cells (androstenedione)

Question 21

What is the function of granulosa cells that surround the primordial germ cell cluster?

Answer 21

to protect the oocytes held within

Question 22

What are the 2 main structures involved in internal reproductive organ formation?

Answer 22

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

Question 23

How is dihydrotestosterone (DHT) produced?

Answer 23

testosterone converted to DHT
(by 5-a-reductase)

occurs in the genital skin

Question 24

What is DHT?

Answer 24

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

Question 25

What happens if there is no DHT available?

Answer 25

female genitalia (external) are formed e.g. in females, there is 5aRED but no testosterone so DHT cannot be made

Question 26

What is the link between 5-a-reducatse and baldness?

Answer 26

5-a-reductase expressed in scalp inhibits hair follicles leads to male-pattern baldness

Question 27

What is gonadal dysgenesis?

Answer 27

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

Question 28

What is sex reversal?

Answer 28

phenotype DOES NOT MATCH genotype

Question 29

What is intersex?

Answer 29

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)

Question 30

What is androgen insensitivity syndrome?

Answer 30

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

Question 31

What is COMPLETE AIS?

Answer 31

AIS = androgen insensitivity syndrome incidence 1:20,000 appear completely female at birth (therefore assigned female gender, even though XY) have undescended testes

Question 32

How is complete AIS usually diagnosed?

Answer 32

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

Question 33

What is PARTIAL AIS?

Answer 33

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

Question 34

What happens with 5-a-reducatase deficiency?

Answer 34

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

Question 35

What is Turner's syndrome?

Answer 35

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

Question 36

What is congenital adrenal hyperplasia?

Answer 36

(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