Sex Determination - Lecture 3 Flashcards
Germ Cells
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
Testicular Germ Cells
Testicular stem cells give rise to spermatocytes which undergo meiosis to become sperm
Alfred Jost experiments
Rabbits
- Remove ovaries –> Female genital formation
- Remove testes –>Wolffian regressian–> Female genital formation
WT1
Wilm’s tumor suppressor/activator gene
- Mutations cause Frasier syndrome and Denys-Drash syndrome
- Gonadal dysgenesis
- Gonadoblastoma
SF1 Human KO
XY karyotype is phenotypically female
- High ACTH, low cortisone, low aldosterone
- Streaked gonads
- Mullerian structures
- Estrogen and progesterone induced menstruation
- Adrenal hyperplasia
46, XX Males
- Male external genitalia
- Highly virilized
- Sterile
- Caused by fault recombination during paternal meiosis leading to SRY gene on X chromosome
46, XY Females
- Pure gonadal dysgenesis
- Streaked gonads
- 30% experience gonadoblastoma or germinomas
- Caused by SRY removal during XY interchange, Y lacks the SRY region
SRY
Sex-determining Region of the Y Chromosome
- testes determining factor
- only sex-determining region on the Y chromosome
Testes Determination Pathway
WT1 and SF1 —> SRY—>SOX9 —> Testes
WT1 and SF1
Sertoli and Leydig cell formation
Sertoli cells lead to production of Anti-Mullerian Hormone and spermatogenesis
SOX9
- Mutations cause campomelic dysplasia (bone abnormalities)
- 46, XY sex reversal with ambiguous genitalia
- Death in neonatal period due to respiratory insufficiency
- Autosomal dominant
AMH
Anti-mullerian hormone
- secreted by sertoli/granulosa cells
- causes regression of Mullerian derivatives
AMH Mutations
- persistent Mullerian duct syndrome
- Males with uterus and fallopian tubes
- AMH Receptor mutations have same phenotypes
AHC (DAX-1)
X p21.3
- Nuclear hormone receptor with DNA binding domain
- Expressed in sertoli cells
AHC Mutations
- Deletions cause congenital adrenal hyperplasia and hypogonadism
- Duplications in XY individuals cause external female genitalia and impaired testicular development
WNT4 Mutations
- Masculinized phenotype
- Primary amenorrhea
- Shortened vagina
- Elevated testosterone levels
- No uterus or fallopian tubes
- Normal ovaries
- Aplastic right kidney
Types of Genital Ambiguity
- 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
46, XX Ovotesticular Disorders of Sex Development
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
46, XX Disorders of Sex Development
Female pseudohermaphrodism
-21-hydroxylase deficiency
OR
-11 beta-hydroxylase deficiency
21-Hydroxylase Deficiency
- 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
11 beta-hydroxylase deficiency
- Causes female pseudohermaphrodism
- Ambiguous genitalia
- Hypertension due to salt retention
- Detected by: Elevated deoxycortisol and deoxycorticotestosterone
- Treated by: Cortisol
Aromatase Deficiency
- Clitoral hypertrophy
- XX and XY can be affected
- Delayed epiphyseal closure
- Primary amenorrhea
- KEY SYMPTOM: Virilization of pregnant mother
- Autosomal recessive
- Treatment: Estrogen
Teratogenic 46, XX Disorders of Sex Development
- If mother is given androgens during pregnancy, fetus may become virilized
- Much less frequent now than in the past
46, XY Disorders of Sex Development
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
45,X/46,XY Mosaicism
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
5 alpha-reductase deficiency
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
Partial androgen insensitivity
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
Complete androgen insensitivity
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
Ovarian maintenance determinants
- Xp11
- Xq13
- BMP15 gene (only expressed in oocytes)
- FMR1 (Fragile X)
- POF1B (premature ovarian failure region)
- PGMRC1 (progesterone membrane receptor)
BMP15
SHEEP
-Heterozygotes have increased fertility
-Homozygotes have decreased fertility
Human mutants are infertile
FMR1 - Fragile X
- 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
FSH Mutations
Follicule stimulating hormone (and receptor)
- Primary amenorrhea
- Infertility
- Small ovaries and uterus
- Autosomal recessive
