SM181 Sex Development Flashcards
What is chromosomal sex?
The chromosome complement at the time of fertilization
What is gonadal sex?
Formation of gonadal tissue and transformation into testis or ovary
Begins very early in gestation (around week 6)
What is phenotypic sex?
Internal and external genitalia and sexual characteristics
Testis-determining genes
SRY (sex-determining region on the Y chromosome)
SOX9, SF1, DAX1, and AMH (anti-mullerian hormone) are also important
Ovary-determining genes
RSPO-1 WNT4
Until what point are male and female genital structures identical?
6 weeks
Where do germ cells come from primordially?
Migrate from the hindgut to the genital ridge
What are Sertoli cells, what do they secrete?
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
What is a Leydig cell? What do they secrete? What stimulates their development?
Endocrine cell adjacent to the seminiferous tubule
Testosterone
beta-hCG
What do the Wolffian ducts form?
Epididymis, vas deferens, seminal vesicle
What stimulates Wolffian ducts?
Testosterone from Leydig cells
What do the Mullerian ducts form?
Fallopian tubes, uterus, upper vagina
SF1
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
SRY
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
SOX9
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)
DAX1
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)
WNT4
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
Mayer-Rokitansky-Kuster-Hauser syndrome
Due to WNT4 mutation
Absent Mullerian structures, mild virilization, high androgen concentrations
AMH (antimullerian hormone)
Produced by Sertoli cells
Regulated by SF1 and SOX9
Causes regression of Mullerian structures
Mutation: 46XY individuals with persistent Mullerian duct syndrome
What side does AMH cause regression on (contralateral or ipsilateral?)
Ipsilateral
5 alpha-Reductase 2
Converts testosterone to dihydrotestosterone (DHT)
Required for masculinization of external genitalia
What does the genital tubercle form in men? Women?
Men: glans penis
Women: clitoris
What does the urogenital sinus form in men? Women?
Men: prostate and prostatic urethra
Women: lower vagina and urethra
What do the urethral folds form in men? Women?
Men: shaft of penis
Women: labia minora
What do the labioscrotal swellings form in men? Women/
Men: scrotum
Women: labia majora
Can the uterus develop if germ cell migration is abnormal? Can the testis?
Uterus: no
Testis: yes
Klinefelter syndrome genotype
47XXY
Turner syndrome genotype
45XO
Mixed gonadal dysgenesis genotype
46XY/45XO (mosaicism)
Klinefelter syndrome findings
Male genitalia, gynecomastia, tall stature with long legs, infertility (azoospermia), insulin resistance, language problems
Turner syndrome findings
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
Complete androgen insensitivity syndrome
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
Partial androgen insensitivity syndrome
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?
5-alpha-reductase deficiency
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
Testicular DSD
46XX
Translocation of SRY onto X chromosome
Normal testicles, male internal and external genitalia
21-hydroxylase deficiency
Ovaries, female internal genitalia, variable external genitalia
Present in infancy with ambiguous genitalia and salt-wasting
Replace cortisol and aldosterone
