Sexual Differentiation And Disorders

Question 1

Mullerian duct

Answer 1

embryonic ducts developing into female internal internal genitalia

Question 2

Wolffian duct

Answer 2

embryonic ducts developing into male internal internal genitalia

Question 3

Sex determining region Y (SRY)

Answer 3

important transcription factor on Y chromosome

Question 4

Primordial germ cell

Answer 4

cells that develop into sperm or oocytes

Question 5

Primitive sex cords

Answer 5

cells that develop into gonadal cells associated with germ cells

Question 6

Mesonephric cells

Answer 6

cells that develop into gonadal cells that produce androgens

Question 7

5-alpha reductase

Answer 7

enzyme involved in development of male external genitalia

Question 8

Gonadal dysgenesis

Answer 8

sexual differentiation is incomplete, usually abnormal development of gonads

Question 9

Sex reversal

Answer 9

phenotype does not match genotype

Question 10

Intersex

Answer 10

some components of both male and female or ambiguous genitalia

Question 11

Sexual Determination

Answer 11

Genetically controlled process dependent on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female. (Contiguous process and consists of several stages)

Question 12

Sexual Differentiation (definition)

Answer 12

The process by which internal and external genitalia develop as male or female. (Contiguous process and consists of several stages)

Question 13

Events in sex differentiation with foetal age

Answer 13

Foetal age weeks
4 - Wolfian Duct development
4.5 - Genital ridge
5 - Primordial Germ Cell migration
6 - Mullerian Duct development
7 - Seminiferous tubules
8 - AMH made so Mullerian regress in male
8 - Leydig cells
9 - First signs of vagina
9 - First meiotic prophase in oogonia
10 - Begin masculinisation of external genitalia
10 - Prostatic buds
10 - Begin regression of Wolffian Duct in female
10 - Testis begins migration
12-14 - Penis developed
17 - First follicles
24 - Vagina developed

Question 14

Gonadal Sex

Answer 14

SRY gene creates the testis.

Sex determining region Y (SRY) switches on briefly during 
embryo development (>week 7) to make the gonad into a 
testis.   In its absence an ovary is formed.

Testis develops cells that make 2 important hormones
which are anti-Mullerian hormone (AMH) and testosterone.

Products of the testis influence further gonadal and
phenotypic sexual development.

Question 15

Gonadal development

Answer 15

After fertilisation a pair of gonads develop which are BIPOTENTIAL.

Their precursor is derived from common somatic mesenchymal tissue precursors called the
genital ridge primordia (3½ - 4½ weeks) on posterior wall of lower thoracic lumbar region.

Question 16

Genital ridge

Answer 16

3 waves of cells 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).

Question 17

1 - Primordial Germ Cell Migration

Answer 17

An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at 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.

Question 18

2 - Primitive sex cords (Sertoli/Granulosa)

Answer 18

Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords.

Male
SRY expression
Penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules.
Eventually become Sertoli Cells which express AMH.

Female
No SRY
Sex cords ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – precursor of ovarian follicle
Eventually become Granulosa cells.

Question 19

3 – Mesonephric cells

Answer 19

These originate in the mesonephric primordium which are just lateral to the
genital ridges.

In males they 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

Question 20

Gonadal sex summary

Answer 20

Invading cells

Male
Primordial germ cells = Spermatozoa
Primitive sex cords = Sertoli cells (SRY, AMH)
Mesonephric cells = Leydig cells (Androgens)

Female
Primordial germ cells = Oocytes
Primitive sex cords = Granulosa cells
Mesonephric cells = Theca cells

Question 21

Internal Reproductive Organs

Answer 21

Mullerian ducts
• most important in female
• inhibited in the male by AMH

Wolffian ducts
• most important in the male stimulated by testosterone
• lack of stimulation by testosterone means regression in female

Question 22

Internal Sexual Differentiation

Answer 22

gonad 
mesonephros 
mullerian duct 
wolffian duct
cloaca 

male =
epididymis
testis 
vas deferens
urinary bladder
seminal vesicle
prostate gland

female =
ovary 
oviduct
degenerating wolffian duct
uterus
urinary bladder
vagina

Question 23

5-α-reductase & External Differentiation

Answer 23

Testosterone is converted in the genital skin to the more potent androgen DHT
(dihydrotestosterone) by 5-a-reductase.

DHT binds to the testosterone receptor, but is more potent than testosterone .

DHT causes differentiation of the male external genitalia:• Clitoral area enlarges into penis
• Labia fuse and become ruggated to form scrotum
• Prostate forms

Question 24

External Differentiation

Answer 24

male and female picture

Question 25

Sex Differentiation Summary

Answer 25

undiff gonad = 1) XY SRY- Testis Sertoli cells: AMH - Regression of mullerian ducts Leydig cells: Testosterone - Differentiation and growth growth of Wolffian duct structures seminal vesicles and vas deferens. Genital skin: Testosterone = DHT - Fusion of labial scrotal folds growth of phallus and prostate. 2) XX Ovary Mullerian ducts differentiate and grow into uterine tubes, uterus and upper 1/3 of vagina. Regression of Wolffian ducts due to lack of androgens. Lack of androgen leads to vagina, labia & clitoris.

Question 26

Disorders of Sexual Differentiation

Answer 26

Gonadal dysgenesis - Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads. Sex reversal - Phenotype does not match genotype, ie may be male genotypically but externally look like a female. Intersex - Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine. Patients prefer to be known as someone with a ‘disorder of sexual differentiation’ or DSD. Terms such as ‘pseudohermaphrodite’ and, ‘testicular feminisation’ are now obsolete.

Question 27

Gonadal dysgenesis - 1

Answer 27

What happens if in an XY individual...Testosterone is made but has no effect. Androgen insensitivity syndrome (AIS) Testes form and make AMH so Mullerian ducts regress. No differentiation of Wolffian ducts No external male genitalia

Question 28

Androgen insensitivity syndrome (AIS)

Answer 28

Complete AIS - incidence 1:20,000 Appear completely female at birth and assigned female gender despite being XY. Have undescended testes. Diagnosis? Usually present with primary amenorrhoea. Lack of body hair is a clue. Ultrasound scan and karyotype with male levels of androgens. Never responded to androgen so appear and often feel female. Partial AIS - incidence unknown as is probably a spectrum Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris. Surgery was universal but now fortunately considered optional or at least best delayed. Decisions made on potential. Very difficult for parents.

Question 29

Gonadal dysgenesis - 2

Answer 29

What happens if in an XY individual...Testosterone is made but not DHT? 5-α-reductase deficiency Testes form and make AMH so Mullerian ducts regress. Wolffian ducts develop No external male genitals.

Question 30

5-α-reductase deficiency

Answer 30

Incidence varies enormously as autosomal recessive and can depend on inter-related marriage. Testes form, AMH acts, testosterone acts. Internal structures form. External structures do not develop. May appear mainly female or may have ambiguous genitalia The degree of the enzyme block varies and so therefore does the presentation. What happens at puberty? Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.

Question 31

Gonadal dysgenesis - 3

Answer 31

What happens if... 45 XO | Turner syndrome

Question 32

Turner syndrome

Answer 32

Turner syndrome: 1:3000 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

Question 33

Gonadal dysgenesis - 4

Answer 33

What happens if XX female is exposed to high levels of androgens in utero? Congenital adrenal hyperplasia

Question 34

Steroidogenesis Adrenal Cortex Pathway Block

Answer 34

diagrams Failure to synthesise cortisol has what effect?

Question 35

Hypothalamic Pituitary Adrenal Axisj

Answer 35

Corticotropin releasing hormone Stimulates pituitary to secrete ACTH. Stimulates rapid uptake of cholesterol into the adrenal cortex. Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion. ``` Hypothalamus CRH Pituitary ACTH Adrenal glands ```

Question 36

Reduced Feedback

Answer 36

diagram

Question 37

Congenital adrenal hyperplasia (CAH)

Answer 37

No SRY so no testes and no AMH. Mullerian ducts remain. Masculinised external genitalia, but androgen levels not usually high enough to fully rescue Wolffian ducts. Congenital adrenal hyperplasia: 1:15,000. Completeness of the block varies. If enzyme absent then children may be wrongly gender assigned at birth, or may have ambiguous genitalia. Also in CAH we need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal. Often require treatment with glucocorticoids to correct feedback.