Sex Determination - Lecture 3

Question 1

Germ Cells

Answer 1

Form from proximal epiblast
Earliest known marker is TNAP (tissue non-specific alkaline phosphatase) - but TNAP KO has no effect on germ cell formation
BMP4 and BMP8b appear to be essential in germ cell formation

Question 2

Testicular Germ Cells

Answer 2

Testicular stem cells give rise to spermatocytes which undergo meiosis to become sperm

Question 3

Alfred Jost experiments

Answer 3

Rabbits

• Remove ovaries –> Female genital formation
• Remove testes –>Wolffian regressian–> Female genital formation

Question 4

WT1

Answer 4

Wilm’s tumor suppressor/activator gene

• Mutations cause Frasier syndrome and Denys-Drash syndrome
• Gonadal dysgenesis
• Gonadoblastoma

Question 5

SF1 Human KO

Answer 5

XY karyotype is phenotypically female

• High ACTH, low cortisone, low aldosterone
• Streaked gonads
• Mullerian structures
• Estrogen and progesterone induced menstruation
• Adrenal hyperplasia

Question 6

46, XX Males

Answer 6

• Male external genitalia
• Highly virilized
• Sterile
• Caused by fault recombination during paternal meiosis leading to SRY gene on X chromosome

Question 7

46, XY Females

Answer 7

• Pure gonadal dysgenesis
• Streaked gonads
• 30% experience gonadoblastoma or germinomas
• Caused by SRY removal during XY interchange, Y lacks the SRY region

Question 8

SRY

Answer 8

Sex-determining Region of the Y Chromosome

• testes determining factor
• only sex-determining region on the Y chromosome

Question 9

Testes Determination Pathway

Answer 9

WT1 and SF1 —> SRY—>SOX9 —> Testes

Question 10

WT1 and SF1

Answer 10

Sertoli and Leydig cell formation

Sertoli cells lead to production of Anti-Mullerian Hormone and spermatogenesis

Question 11

SOX9

Answer 11

• Mutations cause campomelic dysplasia (bone abnormalities)
• 46, XY sex reversal with ambiguous genitalia
• Death in neonatal period due to respiratory insufficiency
• Autosomal dominant

Question 12

AMH

Answer 12

Anti-mullerian hormone

• secreted by sertoli/granulosa cells
• causes regression of Mullerian derivatives

Question 13

AMH Mutations

Answer 13

• persistent Mullerian duct syndrome
• Males with uterus and fallopian tubes
• AMH Receptor mutations have same phenotypes

Question 14

AHC (DAX-1)

Answer 14

X p21.3

• Nuclear hormone receptor with DNA binding domain
• Expressed in sertoli cells

Question 15

AHC Mutations

Answer 15

• Deletions cause congenital adrenal hyperplasia and hypogonadism
• Duplications in XY individuals cause external female genitalia and impaired testicular development

Question 16

WNT4 Mutations

Answer 16

• Masculinized phenotype
• Primary amenorrhea
• Shortened vagina
• Elevated testosterone levels
• No uterus or fallopian tubes
• Normal ovaries
• Aplastic right kidney

Question 17

Types of Genital Ambiguity

Answer 17

• True hermaphrodism - 46, XX with ovarian and testicular tissue
• Female pseudohermaphrodism - 46, XX - internally female, externally male
• Male pseudohermaphrodism - 46, XY - Male gonads, external female genitalia

Question 18

46, XX Ovotesticular Disorders of Sex Development

Answer 18

True hermaphrodism

• Both ovarian and testicular tissue
• Oocytes (not streaked ovaries) and testicles with spermatozoa
• 70% have male external genitalia
• 90% have uterus
• Feminization at puberty
• Some gonadal neoplasia

Question 19

46, XX Disorders of Sex Development

Answer 19

Female pseudohermaphrodism
-21-hydroxylase deficiency
OR
-11 beta-hydroxylase deficiency

Question 20

21-Hydroxylase Deficiency

Answer 20

• Causes female pseudohermaphrodism
• Ambiguous genitalia
• Uterus and ovaries are normal
• Salt wasting (life threatening)
• Detected by: Elevated 17-alpha OH progesterone (shows a block in the enzymatic pathway)
• Treatment: Cortisol, mineral corticoids

Question 21

11 beta-hydroxylase deficiency

Answer 21

• Causes female pseudohermaphrodism
• Ambiguous genitalia
• Hypertension due to salt retention
• Detected by: Elevated deoxycortisol and deoxycorticotestosterone
• Treated by: Cortisol

Question 22

Aromatase Deficiency

Answer 22

• Clitoral hypertrophy
• XX and XY can be affected
• Delayed epiphyseal closure
• Primary amenorrhea
• KEY SYMPTOM: Virilization of pregnant mother
• Autosomal recessive
• Treatment: Estrogen

Question 23

Teratogenic 46, XX Disorders of Sex Development

Answer 23

• If mother is given androgens during pregnancy, fetus may become virilized
• Much less frequent now than in the past

Question 24

46, XY Disorders of Sex Development

Answer 24

Male pseudohermaphrodism
Caused by:
-45,X/46,XY mosaicism
-Testicular biosynthetic errors
-5 alpha-reductase deficiency
-Complete or partial androgen insensitivity
-Agonadia
-Leydig cell agenesis

Question 25

45,X/46,XY Mosaicism

Answer 25

Causes male pseudohermaphrodism - Variable phenotype - Female genitalia --> Ambiguous genitalia - Uterus is usually present - Increased risk for gonadal neoplasia - Most cases in neonatal show female or ambiguous genitalia - Most cases in utero show male genitalia

Question 26

5 alpha-reductase deficiency

Answer 26

Causes male pseudohermaphrodism - Enzyme block at conversion of testosterone to dihydrotestosterone (DHT) - Normal male levels of testosterone but low levels of DHT - Can have male, female, or ambiguous genitalia - Increased T/DHT ratio - Autosomal recessive - Often raised as girls, wind up as male gender idenity, masculinize with puberty

Question 27

Partial androgen insensitivity

Answer 27

Causes male pseudohermaphrodism - Variable extent of genital virilization: labial fusion, clitoral hypertrophy, hypospadias - Feminization at puberty despite T levels higher than normal XY individuals - Caused by: Mutations in androgen receptor may still allow for some binding leading to incomplete virilization

Question 28

Complete androgen insensitivity

Answer 28

Causes male pseudohermaphrodism - 46, XY individuals have bilateral testes - Female external genitalia - Blind ending vagina (no uterus or cervix) - No mullerian derivatives - Cells unable to respond to testosterone - Well developed breasts - 5% develop gonadal neoplasia

Question 29

Ovarian maintenance determinants

Answer 29

- Xp11 - Xq13 - BMP15 gene (only expressed in oocytes) - FMR1 (Fragile X) - POF1B (premature ovarian failure region) - PGMRC1 (progesterone membrane receptor)

Question 30

BMP15

Answer 30

SHEEP -Heterozygotes have increased fertility -Homozygotes have decreased fertility Human mutants are infertile

Question 31

FMR1 - Fragile X

Answer 31

- Intellectual disability - Normal range 5-54 CGG repeats - Premutation range 54-200 CGG repeats (infertile) - Mutation range 200+ repeats (fertile) - 10-15% of premutation carriers have POF

Question 32

FSH Mutations

Answer 32

Follicule stimulating hormone (and receptor) - Primary amenorrhea - Infertility - Small ovaries and uterus - Autosomal recessive