Sexual differentiation and disorders (repro)

Question 1

Sexual determination

Answer 1

Genetically controlled process dependant on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female.

Question 2

Sexual differentiation

Answer 2

The process by which internal and external genitalia develop as male or female.

Question 3

Similarities

Answer 3

The 2 processes are contiguous and consist of several stages

Question 4

Gonadal sex

Answer 4

• 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 5

Gonadal development

Answer 5

• After fertilisation, a pair of gonads develop which are biopotential.
• Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3.5-4.5 weeks) on posterior wall of lower thoracic lumbar region.

Question 6

Genital ridge

Answer 6

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 7

1) Primordial germ cell migration

Answer 7

• An initially small cluster of cells in the epithelium of the yolk. sac which 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 8

2) Primitive sex cords

Answer 8

• Cells from the germinal epithelium, overlying the genital ridge mesenchyme that migrate inwards as columns called the primitive sex cords

Question 9

Primitive sex cords (Sertoli)

Answer 9

Male:

• SRY expression
• penetrate medullary mesenchyme and surround primordial germ cells to form testis cords (precursor of seminiferous tubules)
• eventually become Sertoli cells which express AMH

Question 10

Primitive sex cords (Granulosa)

Answer 10

Female:

• No SRY expression
• 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 11

3) Mesonephric cells

Answer 11

• Originate in the mesonephric primordium which are just lateral to the genital ridges

Question 12

Mesonephric cells in males

Answer 12

Act under the influence of pre-sertoli cells (express SRY) to form:

• vascular tissue
• Leydig cells (synthesise testosterone, do not express STY)
• Basement membrane (contributing formation of seminiferous tubules and rete-testis

Question 13

Mesonephric cells in females

Answer 13

Without the influence of SRY they form:

• vascular tissue
• Theca cells

Question 14

Gonadal sex summary (males)

Answer 14

Invading cells:

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

Question 15

Gonadal sex summary (females)

Answer 15

Invading cells:

• Primordial germ cells = Oocytes
• Primitive sex cords = Granulosa cells
• Mesophrenic cells = Theca cells

Question 16

Mullerian ducts

Answer 16

• most important in female

- inhibited in the male by AMH

Question 17

Wolffian ducts

Answer 17

• most important in the male stimulated by testosterone

Question 18

Internal sexual differentiation (male)

Answer 18

• Epididymis
• Testis
• Vas deferens.
• Urinary bladder
• Seminal vesicle
• Prostate gland

Question 19

Internal sexual differentiation (female)

Answer 19

• Ovary
• Oviduct
• Degenerating Wolffian duct
• Uterus
• Urinary bladder
• Vagina

Question 20

5-alpha-reductase & DHT

Answer 20

• Testosterone converted in the genital skin to androgen DHT (dihydrotestosterone) by 5-alpha-reductase
• DHT binds to testosterone receptor. and is more potent

Question 21

External differentiation by DHT

Answer 21

DHT causes differentiation of the male external genitalia:

• clitorial area enlarges into penis
• Labia fuse and become ruggated to form scrotum
• Prostate forms

Question 22

Sex differentiation. summary (male)

Answer 22

• Undifferentiated gonad develops into Testis due to SRY
• AMH produced by Sertoli cells (regression of mullein ducts)
• Testosterone produced by Leydig cells (differentiation and growth of wolffian duct structures seminal vesicles and vas deferens)
• DHT produced by testosterone in the genital skin (fusion of labial scrotal folds growth of phallus and prostate)

Question 23

Sex differentiation summary (female)

Answer 23

• Undifferentiated gonad develops. into ovary due to lack of SRY
• 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. and clitoris

Question 24

Disorders of sexual differentiation

Answer 24

Gonadal dysgenesis (4 types) - sexual differentiation is incomplete. Usually missing SRY in male, or partial or. complete deletion of second X in female. Used as a general description of abnormal development of 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 with a ‘ disorder of sexual. differentiation’ or DSD
- ‘Pseudohermaphrodite’ and ‘testicular feminisation’ are obsolete

Question 25

Androgen insensitivity syndrome (AIS)

Answer 25

- An XY makes testosterone but it has no effect - Testes form and make AMH so Mullerian ducts regress - Testosterone doesn't act so no differentiation of Wolffian ducts - No DHT forms so no external male genitalia Complete AIS: - Incidence 1 in 20,000 - Appear completely female at birth despite being XY - Undescended testes - Usually present with primary amenorrhea and lack of body hair - Ultrasound shows internal genitalia - Karyotype with male levels of androgens - Doesn't respond to androgens so appears and often feels female Partial AIS: - incidence unknown as its 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 delayed. Decisions made on potential, very difficult for parents

Question 26

5-alpha-reductase deficiency

Answer 26

- An XY produces testosterone and acts on it but doesn't produce DHT - Testes form and AMH is made so Mullerian ducts regress - Testosterone allows Wolffian ducts to develop - Lack of DHT results in no external male genitals - Incidence varies enormously as autosomal recessive and can depend on inter-related marriage - All 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 - Need to assess potential as high testosterone level, will occur at adrenarche and puberty may induce virilisation

Question 27

Turner syndrome

Answer 27

- XO as only have 1 out of 2 X chromsomes - Failure of ovarian function - Incidence 1 in 3,000 - 'Streak' ovaries - 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 28

Congenital adrenal hyperplasia

Answer 28

- An XX is exposed to high levels of androgens in utero - No SRY so no testes and no AMH - Mullerian ducts remain - Masculinised external genitalia. - Androgen levels usually not high enough to fully rescue Wolffian ducts - Incidence 1 in 15,000 - Completeness of. the block varies - If enzyme absent then children may be wrongly gender. assigned at birth or may have ambiguous genitalia - possibility of salt wasting due to lack of aldosterone which can be lethal - Often require treatment with. glucocorticoids to correct feedback

Question 29

Hypothalamic Pituitary Adrenal Axis

Answer 29

- The PVN in the hypothalamus releases Corticotropin releasing hormone (CRH) into the pituitary gland - Stimulates pituitary gland to secrete Adrenocorticotropic hormone (ACTH) - ACTH stimulates rapid uptake of cholesterol into the adrenal cortex - This upregulates cholesterol side-chain cleavage enzyme (P450scc) - This stimulates glucocorticoid (cortisol) secretion

Question 30

Conclusion

Answer 30

- Correct sexual differentiation requires genetic, anatomical and endocrine components - Disorders are rare, but have allowed scientists to understand the requirements for normal development - Diagnosis and treatment of conditions of abnormal sexual differentiation requires a specialist team - Long term functioning of the person is now the primary issue rather than immediate 'corrective' surgery

Question 31

Glossery

Answer 31

- Mullerian duct – embryonic ducts developing into female internal internal genitalia - Wolffian duct - embryonic ducts developing into male internal internal genitalia - Sex determining region Y (SRY) – important transcription factor on Y chromosome - Primordial germ cell – cells that develop into sperm or oocytes - Primitive sex cords – cells that develop into gonadal cells associated with germ cells - Mesonephric cells - cells that develop into gonadal cells that produce androgens - 5-alpha reductase – enzyme involved in development of male external genitalia - Gonadal dysgenesis – sexual differentiation is incomplete, usually abnormal development of gonads - Sex reversal – phenotype does not match genotype Intersex – some components of both male and female or ambiguous genitalia