Intro to Reproduction and Sexual Differentiation

Question 1

What is the difference between sexual determination and sexual differentiation?

Answer 1

Sexual determination is the genetically controlled process dependent on the ‘switch’ on the Y chromosome - chromosomal determination of male or female.

Sexual differentiation is the process by which internal and external genitalia develop as male or female.

Question 2

What are the different ‘levels’ of sex differentiation?

Answer 2

1. genotypic sex
2. gonadal sex
3. phenotypic sex
4. legal sex
5. gender identity

Question 3

After fertilisation a pair of gonads develop which are bi-potential (neither testis or ovaries). What determines differentiation of the bi-potential gonad into a testis or an ovary?

Answer 3

Depends upon the sperm that fertilises the oocyte…

• Y sperm -> testes
• X sperm -> ovary

Question 4

Which gene creates the testis?

Answer 4

SRY gene (on short arm of Y chromosome) - after week 7 it switches on to make the gonad into a testis.

In absence of Y ovaries would develop.

Question 5

What cells does the testis develop and what 2 important hormones do they make?

Answer 5

• Sertoli cells: produce anti-Mullerian hormone (AMH)
• Leydig cells: make testosterone

Question 6

What is the precursor of bipotential gonads that are produced following fertilisation?

Answer 6

Common somatic mesenchymal tissue precursors termed ‘genital ridge primordia’ on posterior wall of lower thoracic lumbar region.

Question 7

What two ducts do bipotential gonads contain?

Answer 7

• Mullerian - for females, develop into internal female genitalia (uterus, upper 3^rd vagina + uterine tubes)
• Wolffian - for males, develop into internal male genitalia (seminal vesicles, vas deferens, prostate)

Question 8

Describe primordial germ cell migration and what they become

Answer 8

They present as a small cluster of cells in the epithelium of the yolk sac, expanding by mitosis (~3 weeks). They then migrate to connective tissue of hindgut to region of developing kidney + on to genital ridge (by 6 weeks).

In males, PGCs -> spermatozoa
In females, PGCs -> oocytes

Question 9

What are Primitive Sex Cords and how do they develop?

Answer 9

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

They depend on SRY expression.

• M: SRY expression -> testis cords -> sertoli cells -> AMH
• F: No SRY expression -> granulosa cells -> estradiol

Question 10

Where do Mesonephric Cells originate from?

Answer 10

The mesonephric primordium which are just lateral to the genital ridges

Question 11

When and what do mesonephric cells differentiate into?

Answer 11

Depend on SRY once again

• MALES: pre-sertoli cells (SRY) -> vascular tissue + Leydig cells + basement membrane (contrib to formation of seminiferous tubules + rete-testis)
• FEMALES: without SRY -> vascular tissue + theca cells

Question 12

What do Theca cells produce?

Answer 12

Synthesize androstenedione, which is a substrate for estradiol production by the granulosa

Question 13

What does AMH do?

Answer 13

Inhibits mullerian ducts (which are important in female) - so will be present in males.

Question 14

What does testosterone do?

Answer 14

Stimulates wolffian ducts - lack of stimulation by testosterone means regression of Wolffians (such as in females)

Question 15

Where is 5-a-reductase found?

Answer 15

Found in the skin of a penis in a male or genital skin.

Question 16

What does 5-a-reductase produce?

Answer 16

Produces a more potent androgen - DHT (dihydrotestosterone) from testosterone.

Question 17

How does DHT bring about differentiation?

Answer 17

It can also bind to testosterone receptors but is more potent.

Causes differentiation of the male external genitalia:

• Clitoral area enlarges into penis
• Labia fuse + become ruggated to form scrotum
• Prostate forms

Question 18

Describe female internal sexual differentiation

Answer 18

• No Y chromosome -> no SRY -> no testis -> no AMH
• Ovary develops (XX)
• (No AMH ->) Mullerian ducts form: uterine tubes, uterus and upper 3rd vagina
• > Upper ends of ducts stay open and form ends of uterine tubes
• > Lower portions fuse to form a single cavity uterus

Question 19

What happens in terms of sexual differentiation in the absence of DHT?

Answer 19

The female external genitalia form instead; clitoria, labia and lower 2/3rds of vagina.

Question 20

What is gonadal dysgenesis?

Answer 20

Sexual differentiation is incomplete due to partial or complete regression of the gonad - AIS, intersex and CAH, all cause gonadal dysgenesis, with individuals having ambiguous genitalia.

Question 21

What is sex reversal?

Answer 21

When the phenotype does not match the genotype ie. may be male genotypically but externally look like a female

Question 22

What is intersex?

Answer 22

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

Question 23

What is Androgen Insensitivity Syndrome (AIS)?

Answer 23

The testes are able to form due to presence of SRY. Make AMH so Mullerian (female duct) regresses. Testosterone is made but it cannot exert an effect due to the absence of receptors. The Wolffian tract/internal male genitalia and external male genitalia (via DHT) therefore do not develop and so the phenotype is female. These individuals present with primary amenorrhoea

Question 24

What is the difference between partial and complete Androgen Insensitivity Syndrome (AIS)?

Answer 24

1. Complete - appear completely female at birth and assigned female gender despite being XY, have undescended testes. Present with primary amenorrhoea + lack of body hair. Appear and feel female.
2. Partial - some penile/scrotal development from ambiguous genitalia to large clitoris. Much more complex for parents and patient.

Question 25

What happens if an XY individual has 5-a-reductase deficiency?

Answer 25

Testosterone is made but not DHT. Develop normal male internal genitalia but the external structures do not develop so may appear female or have ambiguous genitalia. Degree of enzyme block various so therefore does the presentation.

Question 26

What happens in Turner’s Syndrome (45 XO), where 1 of the X chromsomes can be missing?

Answer 26

Ovary develops, Mullerian ducts develop and Wolffian ducts do not. The external genitalia appear female.

However, you get ‘streak’ ovaries = ovarian dysgenesis - illustrates that need 2 Xs for ovarian development.

Uterus and tubes are present but small, other defects in growth + development. May be fertile, many have mosaicism. Hormone support of bones + uterus.

Question 27

What is congenital adrenal hyperplasia (CAH)?

Answer 27

Due to the absence of 21-hydroxylase, which is needed to convert adrenal androgens to cortisol. In the absence of cortisol, ACTH is high and it stimulates adrenal hyperplasia and excessive androgen production, which mimics DHT in females to cause masculinisation of the external genitalia

Question 28

What is meant by ‘salt-wasting’ in CAH?

Answer 28

Due to lack of aldosterone -> can be lethal, need treatment with glucocorticoids to correct feedback.