Development of the Reproductive System and Sex Determination

Question 1

Why is sexual reproduction advantageous ?

Answer 1

• Sexual reproduction creates genetic variety, which in turn is useful for adapting to constantly changing and challenging environments
• Some gene variants may become advantageous in the future under some environmental constraint or insult

Question 2

What are the requirements of sexual reproduction ? What is the result of sexual reproduction ?

Answer 2

• Sexual reproduction requires formation of sperm and oocytes that are haploid
• Fertilization re-establishes the diploid state and chromosomal sex is determined

Question 3

Define sexual differentiation.

Answer 3

• Process by which male and females become structurally and functionally dissimilar.
• If the developing testes (or ovaries) are removed before sexual differentiation, then female differentiation ensues.
• The development of sexually differentiated gonads drives further sexual differentiation of the reproductive tracts

Question 4

Define sexual determination.

Answer 4

The term sex determination is used to describe the initiation of the male differentiation pathway by SRY.

Question 5

What is the aim of specialised structures of the female reproductive tract ?

Answer 5

Specialized structures of the female reproductive tract are needed to nurture the growing embryo and infant after birth.

Question 6

Describe the chromosomal composition of human somatic cells.

Answer 6

Human somatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes (XX or XY)

Question 7

Distinguish between males and females’ chromosomes.

Answer 7

• Female (46, XX) – homogametic

* Male (46, XY) – heterogametic

Question 8

Identify the end result of meiosis of germ cells.

Answer 8

During meiosis germ cells produce gametes with half the number of chromosomes (haploid):
• Oocytes are 23, X
• Spermatozoa are 23, X or 23, Y

Question 9

How can we distinguish between male and female karyotype visibly ?

Answer 9

Male, XY (X smaller than Y)

Female, XX

Question 10

Identify the genetic determinant of sex.

Answer 10

The genetic determinant of sex is the presence or absence of the Y chromosome;
• Presence of “Y” Chrom à male gonads (testes)
• Absence of “Y” Chrom à female gonads (ovaries)

Question 11

Which chromosomes do not impact gonad differentiation ?

Answer 11

Autosomes or “X” chromosomes do not normally influence gonad differentiation

Question 12

Once gonadal differentiation is initiated by the presence or absence of the Y chromosome, what controls further sexual events ?

Answer 12

Once gonadal differentiation is initiated, the developing gonad directs further developmental events that produce sexual dimorphism

Question 13

Describe the structural feature, and genes present of the Y chromosome.

Answer 13

The Y chromosome is small and most of its DNA is condensed

Encodes only ~48 genes -involved in skeletal growth, tooth development, with few genes involved with testes development

Question 14

Which chromosomes are involved with testes development ?

Answer 14

Y chromosome encodes only few genes involved with testes development.

Many of the genes required for testes development are located on autosomes or on the X chromosome. Instead, Y chromosome has a regulatory gene that controls these other developmental genes and so indirectly controls the formation of testes.

Question 15

How was the location of the regulatory gene on the Y chromosome that controls other developmental genes on the X chromosome and autosomes, and so indirectly controls the formation of testes.

Answer 15

The location of this regulatory gene was established in animal studies and by studying subjects with genetic abnormalities.

E.g. Phenotypic women with “XY” genotypes or phenotypic men with “XX” genotypes

Question 16

What happens, to the chromosomes of an XY female ?

Answer 16

Part of the short arm of the Y chromosome is missing or mutated in XY females (due to non-disjunction)

This region contains a gene known as SRY (Sex-determining region of the Y chromosome).

Question 17

What happens to the chromosomes of an XX male ?

Answer 17

XX males have a section of the Y chromosome translocated to an autosome or X chromosome (due to non-disjunction)

This region contains a gene known as SRY (Sex-determining region of the Y chromosome).

Question 18

Given that X and Y chromosomes are different, how can they pair ?

Answer 18

Because the Y chromosome retains regions of homology with the X chromosome that permits pairing during meiosis but errors can occur called non-disjunction

Question 19

Describe the function of the SRY gene. What happens following SRY’s action ?

Answer 19

SRY – encodes a DNA binding protein (transcription factor) that regulates expression of genes on other chromosomes responsible for testes differentiation.

Once gonadal differentiation is initiated, gonadal hormones trigger the cascades that produce sexual dimorphic development of the reproductive tract

Question 20

Identify the steps of gonadal differentiation which are common to both genders.

Answer 20

• Primordial germ cells (PGCs) originate from the epiblast and are first identifiable in the wall of the yolk sac (~2 wks)
• ~10 primordial germ cells first appear but undergo mitotic divisions en route to the genital ridge (~2000 arrive)
• They migrate into the genital ridge driven by chemotaxis
—–
• By 6 wks the PGCs invade the genital ridges and become surrounded by the primitive medullary sex cords
• If the migration of PGCs fails to enter the genital ridge the gonads do not develop
• PGCs have an inductive influence on development of the gonad into ovaries and testes but no role driving sexual dimorphism
• The path of development is determined by the presence of Y chromosome (SRY)

Question 21

Which cell types do ovaries and testes develop from ?

Answer 21

• Testes and ovaries form from two distinct cell types
– Somatic mesenchyme (immature unspecialised CT)
– Primordial germ cells (cells destined to be

Question 22

How long are male and female gonads identical ?

Answer 22

• Gonads are identical in both sexes until the 7th wk of dev (indifferent gonads)

Question 23

Describe the steps of gonadal differentiation in the male (AFTER steps common to both).

Answer 23

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 cords
4) Mesodermal cells differentiate into Sertoli cells in the cords
5) Mesenchyme tissue in interstitial spaces develop into Leydig
cells and start to secrete testosterone by the 8th wk
6) Testosterone then influences the development of the genital ducts and external genitalia
7) By 20 wks, the testis cords are horseshoe-shaped, composed of germ cells and Sertoli cells

Question 24

Describe the steps of gonadal differentiation in the female (AFTER steps common to both).

Answer 24

1) Female development (past 6th week) due to the absence of Y chromosome, leads to degeneration of medullary cords/primitive sex cords
2) Cortical cords form from proliferating surface epithelium forming distinct cell clusters around germ cells by 12 wks
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 25

Describe the steps of genital ducts formation.

Answer 25

• At 7-8 wks embryos acquire dual ductal systems that are precursors to the male and female internal genitalia
• Wolffian (mesonephric) (connected to mesonephros, of developing kidney) ducts give rise to the male genital ductal system
• Müllerian (paramesonephric) (connected to urogenital sinus) ducts give rise to the female genital ductal system
(both^ of these present in indifferent stage)
• The developmental path taken depends on hormones secreted by the developing testis NOT the ovary

Question 26

Describe the steps in the development of the male internal genitalia.

Answer 26

1) In males, SRY acts in conjunction with other transcription factors such as SOX9 and SF-1 to stimulate the differentiation of Sertoli and Leydig cells
2) Sertoli cells then express anti-Müllerian hormone (AMH) which leads to regression of the Müllerian/paramesonephric ducts and prevents development of female structures
3) Leydig cells start secreting testosterone which supports the the development of the mesonephric ducts and leads to virilisation

After testes descent:

• Paramesonephric ducts have regressed, remnant is paramesonephric tubercle (all that’s left of female duct system)
• Epigenital tubules develop and contact with the cord of testes. Later form the efferent ductules.
• Mesonephric duct becomes highly convoluted, forming epididymis.
• Rest of mesonephric duct obtains thick muscular coat and becomes vas deferens and seminal vesicle.

Question 27

Describe the steps in the development of the female internal genitalia.

Answer 27

After ovarian descent:
• In absence of any hormones mesonephric ducts degenerate and paramesonephric ducts develop forming fallopian tubes
• WNT4 (ovary-determining gene) up-regulates DAX1, which inhibits the function of SOX9, preventing the male program
• WNT4 also regulates the expression of other genes responsible for ovarian differentiation, but many target genes have not been identified
• Estrogen stimulates the paramesonephric ducts to develop into the female internal genitalia
—–
• 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 20 wks, vaginal outgrowth is complete and expands around the end of the uterus

Question 28

Describe the state of the cortical, and medullary cord in the male, and female.

Answer 28

MALE

• No cortical cords
• Medullary cords develop

FEMALE

• Cortical cords develop
• Medullary cords degenerate

Question 29

Are external genitalia unipotent, or bipotent initially ?

Answer 29

External genitalia initially bipotent

Question 30

What is the developmental path taken by external genitalia (male or female) dependant on ?

Answer 30

Developmental path taken depends on the PRESENCE or ABSENCE of androgens

• Presence of androgens = MALE
• Absence of androgens (default) = FEMALE

Question 31

What type of problem can result in inappropriate gonadal development ?

Answer 31

Chromosomal abnormalities can cause inappropriate gonadal development (and also can have further effects on body development)

Question 32

Identify the main disorders of chromosomal sex.

Answer 32

• Turner’s Syndrome (45, X0)
• Klinfelter Syndrome (47, XXY)
• Triple X Syndrome (47, XXX)
• XYY Syndrome (47, XYY)
• Sex reversed

Question 33

Describe the main features of Turner’s Syndrome.

Answer 33

(45, X0)

• Oocytes (female germ cells) degenerate since two “X” chromosomes are needed for full ovarian development – leading to “Streak ovary”
• Deficiency in ovarian steroids
• Lack of secondary sex characteristics and infertility
• Other developmental defects: short stature, webbed neck and skeletal deformities

Question 34

State the number of autosomes, sex chromosomes, and gonads in each of the following:

• Turner’s Syndrome
• Klinefelter Syndrome
• Triple X Syndrome
• XYY Syndrome
• Sex reversed

Answer 34

• Turner’s Syndrome: 44 autosomes, XO, ovary
• Klinefelter Syndrome: 44 autosomes, XXY, testis
• Triple X Syndrome: 44 autosomes, XXX, ovary
• XYY Syndrome: 44 autosomes, XYY, testis
• Sex reversed: 44 autosomes, XX(SXR), testis (translocation of SRY gene on autosome or X chromosome, meaning testes develop)

Question 35

Describe the main features of Klinefelter’s Syndrome.

Answer 35

• Develop male phenotype
• Incomplete virilization and breast enlargement after puberty
• Small testes with decreased spermatogonia

Question 36

What defect occurs if the sex chromosomes are XXY or XXX with 66 autosomes ? Which gonads would each of these yield otherwise ?

Answer 36

Triploidy (not viable)
XXX: ovary
XXY: testis

Question 37

Identify disorders of sexual differentiation (DSD).

Answer 37

• Pseudo-hermaphroditism
• Androgen-Insensitivity Syndrome
• Congenital Adrenal Hyperplasia

Question 38

Describe the main features of Pseudo-hermaphroditism.

Answer 38

• Individual with gonads appropriate to their genotype but external genitalia of the opposite sex
• Abnormality in endocrine signalling between the gonads and developing tissues
• One such syndrome is Androgen-insensitivity Syndrome (previously called testicular feminization syndrome)
• Individuals have a 46, XY karyotype

Question 39

Describe the main features of Androgen-Insensitivity Syndrome.

Answer 39

• Testes are initially normal but the tissues lack (or have a dysfunctional) androgen receptor so are unable to respond to testosterone
• The mesonephric ducts degenerate without the support of androgens (unable to sense the signal)
• The testes secrete normal amounts of AMH, so female ducts degenerate – NO DUCTs at all
• Female external genitalia develops but have undescended testes

Question 40

Describe the main features of congenital adrenal hyperplasia.

Answer 40

• Genotype is XX and ovaries develop
• However, foetal adrenals are over-active
• Secrete large amounts of steroid hormones some of which have androgenic action
• Causes development of mesonephric ducts and formation of male external genitalia
• No AMH is secreted therefore female ducts persist – Therefore BOTH ductal systems are present

Question 41

Summarise sexual differentiation.

Answer 41

Refer to diagram on slide 44 of lecture slides.

Question 42

Identify the female internal genitalia.

Answer 42

vagina, uterus, Fallopian tubes, and ovaries.

Question 43

Identify the male internal genitalia.

Answer 43

seminal vesicle, testes, vas deferens, epididymis, prostate, bulbourethral gland, and ejaculatory duct.

Question 44

Identify the male external genitalia.

Answer 44

penis, urethra, and scrotum.

Question 45

Identify the female external genitalia.

Answer 45

 Mons pubis
 Labia majora
 Labium minora
 Clitoris
 Vaginal vestibule
 Hymen
 Vestibular bulbs
 Greater vestibular gland