4/8 Normal Development and Disorders of Sexual Dev

Question 1

What is the sequence of sexual differentiation? (4 steps)

Answer 1

1. Genetic sex
2. Formation of gonads
3. Formation of ductal system (vas def/epididymus; uterus/vag)
4. Differentiation of external genitalia

Sex->Gonads->Ducts->External

Question 2

In normal male sexual differentiation, what drives an undifferentiated gonad to become a testicle?

How does this testicle cause the regression of the Mullerian ductal system?

Answer 2

Testicular determinants on the Y chromosome (SRY).

Causes testicular development –> seminiferous tubules, sertoli cells –> produce MIF –> causes Mullerian ductal system to regress.

Question 3

Once testicles start to develop, how do they promote descent into the scrotum?

Answer 3

Testicular development –> Testicular cords, seminiferous tubules, sertoli cells -> Fetal Leydig cells -> Testicular descent -> Scrotal location of testes

Question 4

Once testicles start to develop, what is the process of promoting the Wolffian system and creation of testosterone?

Answer 4

Testicular development –> Testicular cords, seminiferous tubules, sertoli cells -> Fetal Leydig cells -> Produce testosterone ->Wolffian system developed.

Due to testosterone from the Fetal Leydig cells, DHT and maximum testosterone eventually created -> masculinization

Question 5

Gonads: at what point in development do they appear?

when do primordial germ cells move to them?

Answer 5

Appear in the 5th week as protuberances over mesonephric ducts

at 4-6 weeks, primordial germ cells move to the protuberances

Question 6

at 6 weeks’ gestation, what state are the gonads in? What cell types are present?

what ductal systems are present?

What is the state of the external genitalia?

Answer 6

Gonads are indifferent (bipotential) at 6 wks. Three cell types present: Germ cells, Mesenchymal cells (become Theca or Leydig), Epithelial cells (become Granulosa or Sertoli)

Both ductal systems are present: Wolffian and Mullerian

External genitalia also indifferent.

Question 7

Indifferent Mesenchymal cells become what in females? males?

Indifferent Epithelial cells become what in females? males?

Answer 7

Mesenchymal cells –> Theca (F) or Leydig (M)

Epithelial cells –> Granulosa (F) or Sertoli (M)

Question 8

What is the evidence that SRY is actually the testicular determining factor?

Answer 8

(Sex-determining Region on Y – on short arm of Y chromo)

Evidence: it is deleted or mutated in XY females

it is present in XX males

Question 9

What are the 5 components required for normal male differentiation?

Answer 9

(1) testicular determinant genes are expressed
(2) there is bilateral gonadal elaboration of MIS
(3) bilateral gonadal production of testosterone
(4) it is converted at the end organ to dihydrotestosterone
(5) there must exist functional receptors for all of the appropriate proteins including LH, MIS, and androgens.

Question 10

Without SRY, what will the gonad turn into?

Answer 10

Gonad will turn into an ovary rather than a testis

Question 11

What is the sequence of normal female gonadal development?

What is required?

Answer 11

Without SRY, the indifferent gonad –> ovarian development and cortical proliferation.

Then Meiosis 1 (oocytes) –> Primordial follicles

Then Ovarian Determinant Genes appear -> Primary Follicles

-> Max number of germ cells (7m), eventually decreases to 2m germ cells by birth.

Only requirements: absence of SRY, ovarian determinant gene action

Question 12

What composes the internal ductal system in males? females?

Answer 12

Males: epididymus, vas deferens, seminal vesicles

Females: fallopian tubes, uterus, vagina

Question 13

What causes the differentiation of the internal ductal system to a male phenotype? to a female phenotype?

Answer 13

Male: when MIH (aka AMH, MIS) is produced by Sertoli cells (in testes), the Mullerian system will regress and Wolffian system will develop

Female: when the gonad becomes an ovary, no MIH is produced. Therefore the Mullerian system develops and the Wolffian system regresses.

Question 14

In order for the Wolffian ductal system to develop, MIF is required. What else is required?

Answer 14

Testosterone is required for the Wolffian ductal system to develop. MIF causes the regression of the Mullerian system; testosterone is still needed to develop the Wolffian.

Question 15

In order for the Mullerian ductal system to develop, what is required?

Answer 15

Just the absence of MIF so that it does not regress. Doesn’t need anything additional in order to develop.

Question 16

What processes create the vagina, uterus, and tubes from the Mullerian ductal system? What part of the Mullerian ductal system is involved?

Answer 16

Paramesonephric bulbs

• Elongation
• Lateral fusion
• Canalization (makes internal spaces)
• Septal resorption

Question 17

Male development: what causes masculinazation of the external genitalia?

What enzyme is required?

Answer 17

Dihydroxytestosterone (DHT) causes the masculinization of external genitalia.

Testosterone –> DHT using enzyme 5-a-reductase.

Question 18

What are the components of the undifferentiated external genitalia? what does each part become?

Answer 18

Genital tubercle –> penis or clitoris

Urogenital slit –> urethra

Labial/scrotal folds –> scrotum or labia

(this pic was taken from a veterinary site, but how different can it be??)

Question 19

Repeated question: After germ cell migration, complete normal male sexual differentiation requires what 4 things?

Answer 19

1. Testicular determinant gene action (SRY)
2. Bilateral gonadal elaboration of MIS
3. Gonadal androgen steroidogenesis
4. Competent androgen receptors at the target organ

Question 20

Does female genital differentiation require the presence of estrogen?

Answer 20

Does not appear to. Estrogen definitely required for puberty, but not for genital differentiation.

Question 21

What causes the indifferent external genitalia to become feminized?

Answer 21

The absence of DHT.

Question 22

Incompletely masculinized males (aka male pseudohermaphroditism): what are some possible etiologies?

Answer 22

• androgen insensitivity
• deficiency in 5-a-reductase (catalyzes testosterone -> DHT)
• testosterone synthesis defects

Question 23

Masculinized females (aka female pseudohermaphroditism): what are some possible etiologies?

Answer 23

• Congenital adrenal hyperplasia
• Maternal androgen intake or production

Question 24

Two disorders of gonadal development?

Answer 24

• True hermaphrodites (have both male and female systems)
• Turner’s syndrome

Question 25

List again the 4 steps of sexual differentation: add in the driving force for each step

Answer 25

1. Genetic Sex (XX v. XY)
2. Formation of Gonads (SRY)
3. Formation of Ductal systems (MIH)
4. Differentiation of External Genitalia (DHT)

Question 26

What does this depict?

Answer 26

White/pink line on right: ovarian streak such as we might see with a 45X karyotype

Question 27

If a girl is found to have an absent kidney, we should be suspicious for what other possible developmental malformations?

Answer 27

Ductal systems tend to form or mis-form together – this system is guided by the GI/kidney system, so renal anomalies are not surprising. May also have horseshoe kidney, duplication errors, frequent UTIs

Completion of mullerian development –> uterus, vagina, fallopian tubes. With malformation, usually have absence of vagina, no uterus, but almost always have Fallopian tubes.

Would she be able to reproduce? YES, harvest eggs from ovaries, use surrogate.

Question 28

If the genitalia are ambiguous, and 1 or both gonads have descended into the labioscrotal pouch, what can we conclude about the child’s 21-hydroxylase status?

Answer 28

The child does not have 21-hydroxylase deficiency!

Question 29

What genetic pattern does CAH follow?

Androgen insensitivity?

5-a-reductase deficiency?

(more for boards)

Answer 29

CAH: Auto recessive

Androgen insensitivity: X-linked recessive

5-a-reductase deficiency: Auto recessive