sexual differentiation

Question 1

Sexual determination

Answer 1

Genetically controlled process dependent 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

Gonadal sex

Answer 3

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 4

Gonadal development

Answer 4

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 5

Genital ridge 3 waves of cells

Answer 5

1. Primordial germ cells
2. Primitive sex cords
3. Mesonepheric cells

Question 6

Primordial germ cells

Answer 6

Become Sperm (male) or Oocytes (female).

Question 7

Primitive sex cords

Answer 7

Become Sertoli cells (male) or Granulosa cells (female).

Question 8

Mesonepheric cells

Answer 8

Become blood vessels and Leydig cells (male) or Theca cells (female).

Question 9

1. Primordial Germ cell migration

Answer 9

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 10

2. Primitive sex cords (Sertoli/Granulosa)

Answer 10

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

Question 11

SRY

Answer 11

Expressed in males - Penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules.
Eventually become Sertoli Cells which express AMH.

Question 12

SRY and females

Answer 12

There is no SRY
Sex cords ill-defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – the precursor of ovarian follicle
Eventually, become Granulosa cells

Question 13

Male mesonephric cells

Answer 13

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

Question 14

Female mesonephric cells

Answer 14

In females without the influence of SRY they form…
• Vascular tissue
• Theca cells

Question 15

Mullerian ducts

Answer 15

• most important in female

* inhibited in the male by AMH

Question 16

Wolffian ducts

Answer 16

• most important in the male stimulated by testosterone

* lack of stimulation by testosterone means regression in female

Question 17

5-α-reductase & External Differentiation

Answer 17

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 18

Gonadal dysenesis

Answer 18

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.

Question 19

Sex reversal

Answer 19

Phenotype does not match genotype, ie may be male genotypically but externally look like a female.

Question 20

Intersex

Answer 20

Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.

Question 21

DSD

Answer 21

Disorder of sexual differentiation

Question 22

AIS

Answer 22

Androgen insensitivity syndrome
Appear completely female at birth and assigned female gender despite being XY.
Have undescended testes.

Question 23

Diagnosis for AIS=

Answer 23

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.

Question 24

Partial AIS

Answer 24

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 25

5-a-reductase deficiency

Answer 25

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.

Question 26

What happens at puberty with 5-a-reductase deficiency?

Answer 26

Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.

Question 27

Turner syndrome

Answer 27

* 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 28

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

Answer 28

Congenital adrenal hyperplasia

Question 29

Hypothalamic pituitary adrenal axis

Answer 29

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

Question 30

Congenital adrenal hyperplasia (CAH)

Answer 30

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.