SM181 Sex Development

Question 1

What is chromosomal sex?

Answer 1

The chromosome complement at the time of fertilization

Question 2

What is gonadal sex?

Answer 2

Formation of gonadal tissue and transformation into testis or ovary

Begins very early in gestation (around week 6)

Question 3

What is phenotypic sex?

Answer 3

Internal and external genitalia and sexual characteristics

Question 4

Testis-determining genes

Answer 4

SRY (sex-determining region on the Y chromosome)

SOX9, SF1, DAX1, and AMH (anti-mullerian hormone) are also important

Question 5

Ovary-determining genes

Answer 5

RSPO-1 WNT4

Question 6

Until what point are male and female genital structures identical?

Answer 6

6 weeks

Question 7

Where do germ cells come from primordially?

Answer 7

Migrate from the hindgut to the genital ridge

Question 8

What are Sertoli cells, what do they secrete?

Answer 8

Sustentacular cells associated with the seminiferous tubule that are nvolved in male gonadal differentiation

Secretes AMH (anti-mullerian hormone) which causes regression of the Mullerian (paramesonephric) ducts

Question 9

What is a Leydig cell? What do they secrete? What stimulates their development?

Answer 9

Endocrine cell adjacent to the seminiferous tubule

Testosterone

beta-hCG

Question 10

What do the Wolffian ducts form?

Answer 10

Epididymis, vas deferens, seminal vesicle

Question 11

What stimulates Wolffian ducts?

Answer 11

Testosterone from Leydig cells

Question 12

What do the Mullerian ducts form?

Answer 12

Fallopian tubes, uterus, upper vagina

Question 13

SF1

Answer 13

Affects all three levels of the HPG axis

Regulates ACTH receptor, LH, AMH

Homozygous mutation: gonadal dysgenesis and adrenal insufficiency

Heterozygous mutation: gonadal dysgenesis without adrenal insufficiency

Question 14

SRY

Answer 14

Sex-determining Region of the Y chromosome

Induces Sertoli cell differentiation, migration of mesonephric cells into the genital ridge, proliferation of cells in the genital ridge, and male-specific vasculature development

Sex reversal in 46XX males with SRY and 46XY females without SRY

Question 15

SOX9

Answer 15

Upregulated after SRY, expressed in Sertoli cells, regulates AMH

Induces chondrogenesis

Haploinsufficiency leads to XY gonadal dysgenesis (sex reversal) and campomelic dysplasia (skeleton development defects)

Question 16

DAX1

Answer 16

Dose-sensitive sex reversal

Mutation gives you Adrenal Hypoplasia Congenita, hypogonadotropic hypogonadism, and impaired spermatogenesis

Expressed in hypothalamus, pituitary, testis, adrenal cortex, and ovary

Duplication gives you 46XY sex reversal (dose-dependent)

Question 17

WNT4

Answer 17

Females: Mullerian duct formation, maintenance of oocytes, suppress Leydig cells

Males: proper testis vasculature, organization of sex cords

Heterozygous human WNT4 mutations seen in 46XX females with Mayer-Rokitansky-Kuster-Hauser syndrome

Question 18

Mayer-Rokitansky-Kuster-Hauser syndrome

Answer 18

Due to WNT4 mutation

Absent Mullerian structures, mild virilization, high androgen concentrations

Question 19

AMH (antimullerian hormone)

Answer 19

Produced by Sertoli cells

Regulated by SF1 and SOX9

Causes regression of Mullerian structures

Mutation: 46XY individuals with persistent Mullerian duct syndrome

Question 20

What side does AMH cause regression on (contralateral or ipsilateral?)

Answer 20

Ipsilateral

Question 21

5 alpha-Reductase 2

Answer 21

Converts testosterone to dihydrotestosterone (DHT)

Required for masculinization of external genitalia

Question 22

What does the genital tubercle form in men? Women?

Answer 22

Men: glans penis

Women: clitoris

Question 23

What does the urogenital sinus form in men? Women?

Answer 23

Men: prostate and prostatic urethra

Women: lower vagina and urethra

Question 24

What do the urethral folds form in men? Women?

Answer 24

Men: shaft of penis

Women: labia minora

Question 25

What do the labioscrotal swellings form in men? Women/

Answer 25

Men: scrotum Women: labia majora

Question 26

Can the uterus develop if germ cell migration is abnormal? Can the testis?

Answer 26

Uterus: no Testis: yes

Question 27

Klinefelter syndrome genotype

Answer 27

47XXY

Question 28

Turner syndrome genotype

Answer 28

45XO

Question 29

Mixed gonadal dysgenesis genotype

Answer 29

46XY/45XO (mosaicism)

Question 30

Klinefelter syndrome findings

Answer 30

Male genitalia, gynecomastia, tall stature with long legs, infertility (azoospermia), insulin resistance, language problems

Question 31

Turner syndrome findings

Answer 31

Female genitalia, ovarian dysgenesis (streak ovaries), short stature, shield shaped chest with widely-spaced nipples, cardiac abnormalities (coarctation of aorta, bicuspid aortic valve), webbed neck

Question 32

Complete androgen insensitivity syndrome

Answer 32

46XY Androgen receptor mutation Testes, female external genitalia, absence of Mullerian duct derivatives, sparse pubic hair, spontaneous pubertal breast development (aromatization of androgens to estrogens) Inguinal/labial masses, amenorrhea Raise as female

Question 33

Partial androgen insensitivity syndrome

Answer 33

46XY Androgen receptor mutation but retain some response Infancy with ambiguous genitalia Testes, absent Mullerian derivatives, Wolffian ducts abnormal, undervirilized external genitalia Enlargement of phallus at puberty but still small Raise as male or female?

Question 34

5-alpha-reductase deficiency

Answer 34

Impaired conversion of testosterone to DHT 46XY with undervirilization Testes, Wolffian structures, absent Mullerian structures, small phallus, urogenital sinus with perineal hypospadias, blind vaginal pouch raise Progressive virilization at puberty Low fertility High in Papua New Guinea, Turkey, Dominican, Middle East

Question 35

Testicular DSD

Answer 35

46XX Translocation of SRY onto X chromosome Normal testicles, male internal and external genitalia

Question 36

21-hydroxylase deficiency

Answer 36

Ovaries, female internal genitalia, variable external genitalia Present in infancy with ambiguous genitalia and salt-wasting Replace cortisol and aldosterone