6. Development of the reproductive system and sex determination

Question 1

What is sexual differentiation?

Answer 1

The process by which male and females become structurally and functionally dissimilar

Question 2

What is sex determination?

Answer 2

The initiation of the male differential pathway by SRY

Question 3

The genetic determinant of the sex is the presence/absence of the…

Answer 3

Y chromosome
Presence = Male gonads
Absence = Female gonads

Question 4

Role of the Y chromosome in chromosomal sex

Answer 4

Encodes only about 48 genes involved in:

• Skeletal growth
• Tooth development
• Few genes involved with testes development

Question 5

Where are the genes required for testes development located?

Answer 5

Autosomes or on the X chromosome

Y chromosome has regulatory gene that control these other developmental genes and so indirectly controls the formation of testes

Question 6

How does non-disjunction occur between the X and Y chromosome?

Answer 6

The Y chromosome retains regions of homology with the X chromosome that permit pairing during meiosis but errors can occur called non-disjunction.
When part of the short arm of the Y chromosome is missed or mutated in XY females.

Question 7

What is SRY?

Answer 7

Gene that is the sex-determining region of the Y chromosome
Encodes a DNA binding proteins (TF) that regulates expression of genes on other chromosomes responsible for testes differentiation

(So XX males have the SRY containing section of the Y chromosomes translocated to the an autosome or X chromosome)

Question 8

Testes and ovaries form from which two distinct cell types?

Answer 8

Somatic mesenchyme

Primordial germ cells (PGCs): Originate from epiblast and are identifiable in the wall of the yolk sac

Question 9

How do the gonads form from weeks 0-7?

Answer 9

Genital ridge is formed by proliferation of the surface epithelium and condensation of mesenchyme forming sex cords.

PCGs migrate into the genital ridge driven by chemotaxis. By 6 weeks the PCGs invade the genital ridges and become surrounded by the primitive medullary sex cords.

Are identical until this point for both males and females

Question 10

Male gonadal differentiation?

Answer 10

1. Under the influence of the SRY gene, primitive sex cords proliferate and penetrate the medulla forming testis cords
2. Testis cords become looped. Contact with the ingrowing mesonephric tubule called Rete testis
3. Primordial germ cells come to reside within the developing testis cord. Mesodermal cells differentiate into Sertoli cells in the cords. Mesenchyme tissue in interstitial spaces develop into Leydig cells and start to secrete testosterone by the 8th week
4. Testosterone influences the development of the genital ducts and external genitalia.
5. By 20 weeks the testis cords are horseshoe-shaped, composed of germ cells and Sertoli cells.

Question 11

Female gonadal differentiation?

Answer 11

1. Female development (after 6th week) is influenced by the absence of Y chromosome. This leads to degeneration of primitive sex cords.
2. A second set of cords form from mesenchyme (cortical cords) and by 12 weeks these form distinct cell clusters around the germ cells.
3. Cells proliferate and surround each oogonium (germ cell) with epithelial layer of follicular cells – forming primordial follicles
4. Germ cells are absolutely required for the formation of the ovarian follicles

Question 12

How are genital ducts formed?

Answer 12

At 7-8 weeks embryo’s acquire dual ductal systems that are precursors to the male and female internal genitalia

Wolffian (mesonephric) ducts give rise to the male genital ductal system

Müllerian (paramesonephric) ducts give rise to the female genital ductal system

The developmental path taken depends on hormones secreted by the developing testes not the ovary.

Question 13

How is the internal genitals of the male system developed?

Answer 13

In males, SRY acts in conjunction with other transcription factors: SOX9 and SF-1 (steroidogenic factor 1). These stimulate the differentiation of Sertoli and Leydig cells

• SERTOLI CELLS then express anti-mullerian hormone (AMH) which leads to regression of the Mullerian ducts and prevents development of female structures
• LEYDIG CELLS start secreting testosterone which supports the development of the Wolffian ducts and leads to virilisation.

Summary: Medullary cords develop and no cortical cords develop

Question 14

What is the hormonal control of the development of the female internal genitalia?

Answer 14

In absence of any hormones Wolffian ducts degenerate and Mullerian ducts develop forming fallopian tubes

WNT4 (ovary-determining gene) actions:

1. Upregulates DAX1, which inhibits the function of SOX9, preventing the male program
2. Regulates the expression of other genes responsible for ovarian differentiation

Oestrogen stimulates the Mullerian ducts to develop into female internal genitalia.

Summary: Medullary cords degenerate and cortical cords develop

Question 15

Development of female internal genitalia?

Answer 15

The lower vagina forms from the paramesonephric tubercle (a region called the sinovaginal bulbs)
Two evaginations grow out from the pelvic side and proliferate forming the vaginal plate
By 20wks vaginal outgrowth is complete and expands around the end of the uterus

Question 16

What determines the path which external genetalia takes in development?

Answer 16

Presence or absence of androgens

Question 17

What is the effect of Turner’s syndrome on oocytes?

Consequences?

Answer 17

Turner's syndrome (45,XO)
--> Oocytes (female germ cells) degenerate since two X chromosomes are needed for full ovarian development. 
Results in..
-"Streak ovary"
-Deficiency in ovarian steroids
-Lack of secondary sex characteristics 
-Infertility 
-Developmental defects: Short stature, webbed neck and skeletal deformities

Question 18

What is Klinfelter’s syndrome?

Answer 18

47, XXY
Development of male phenotype
Incomplete virilization and breast enlargement after puberty
Small testes with decreased spermatogonia

Question 19

What is sex reversed syndrome?

Answer 19

44, XX SXR with Testes

Inconsistency between gonadal sexuality and chromosome sexuality

Question 20

Name examples of disorders of sexual differentiation?

Answer 20

Pseudohermaphroditism e.g. Androgen-insensitivity syndrome

Congenital adrenal hyperplasia

Question 21

What is pseudohermaphroditism?

Answer 21

Individuals with gonads appropriate to their genotype but external genitalia of the opposite sex
Caused by abnormality in endocrine signally between the gonads and developing tissues

Karyotype: 46, XY

Question 22

Example of pseudohermaphroditism?

Answer 22

Androgen-insensitivity syndrome

Question 23

What is Androgen-insensitivity syndrome ?

Answer 23

Testes are initially normal but the tissues lack androgen receptor so are unable to respond to testosterone
The Wolffian ducts degenerate without the support of androgens
The testes secrete normal amounts of AMH (prevent female duct development) so…. NO DUCTS DEVELOP

Phenotype: Female external genitalia develops but have undescended testes

Question 24

What is congenital adrenal hyperplasia?

Answer 24

Genotype: XX
Phenotype: Ovaries develop

Malfunction: Fetal adrenals are overactive. Secrete large amounts of steroid hormones some of which have androgenic action.
–>Development of Wolffian ducts and formation of male external genitalia
No AMH is secreted therefore female ducts persists.
–> Two ductal systems are present