Sexual differentiation Flashcards
Sex determination
Commitment of the indifferent gonad to develop as testis or ovary
Genetically controlled depending on developmental time and gene expression
Basic requirements for normal sexual development
- Presence of normal sex chromosome complement
- The presence of SRY on the Y chromosome is necessary for male dev
- The presence of 2 X chromosomes and no SRY is necessary for female dev - Correct function of genes within the sex determination cascade
- The correct response of hormone receptors
Sex determination in the early embryo
Until wk 5-7 embryo said to be sexually indifferent
WK6
- SRY upregulates SOX9 a testis specific gene that initiates differentiation of pre-sertoli cells (repressed in females
- Aggregation of pre-sertolicells around primary sex cords and AMH production
WK7
-Formation of seminiferous tubules
WK8
- AMH production by sertoli cells causes mullerian duct regression
- Binds AMH type II receptors in surrounding mesechyme causing apoptosis of mullerian epithelial cells
WK9
- Mesenchyme separating seminiferous cords differentiates into interstitial cells (Leydig)
- Concomitant leydig cell proliferation and increase in steroidogenesis (testosterone production)
- Stabilisation of Wolffian ducts
- Differentiate into vas deferens, seminal vesicles, spididymis
Differentiation of external genitalia regulated by dihydrotestosterone (5alpha reductase)
Denys-Drash syndrome
WT1
Disruption of seminiferous tubule and somatic cell apoptosis
XY sex reversal
Failure of genital ridge formation
Campomelic dysplasia
SOX9
XY sex reversal (LOF) or XX sex reversal (GOF)
Abnormal sertoli cell differentiation
Sex reversal- males
Male phenotype with female karyotype
80% have small segment of Y chromosome including SRY in place of distal X (unbalanced sex chr translocation)
XX males are infertile
20% have no SRY and partial male/ambiguous sexual development
Sex reversal- females
XY females usually carry a copy of SRY on the Yp
- Swyer syndrome
- Androgen insensitivity syndromes
Swyer syndrome
Mutation in SRY or other gene in male sex determination cascade
Also known as pure gonadal dysgenesis
- streak gonads
- female external genitalia
- failure of puberty/infertile
- 30% risk of developing gonadoblastoma (removal of gonads recommended)
Complete androgen insensitivity
Also known as testicular feminisation
- Disorder of androgen function
- Female external genitalia, short/absent vagina
- Normal dev of female characteristics at puberty
- Infertile
- Intra-abdominal testes
- 2% risk gonadoblastoma
Androgen resistance syndromes
very rare enzyme defects e.g. 5alpha reducatase or 17alpha hydroxylase deficiency
46,XY karyotype
Bilateral testes and normal secretion of testosterone
Female external genitalia
Virilisation of external genitalia at puberty
Gynaecomastia
Reduced spermatogenesis
CAH
Enzyme deficiencies affecting steriodogenesis
Classic CAH
- 21-hydroxylase deficiency
- XX karyotype= masculinisation of external genitalia
- XY karyotype= normal genitalia
- Treat during pregnancy with dexamethasone and after birth with hormones
both sexes if untreated= salt wasters (can lead to death in first few weeks)
Autosomal sex reversal- female phenotype
XY karyotype with autosomal imbalance in regions carrying other genes in male determining cascade
e.g. deletions/unbalanced translocations of
9p24
9q33
10q26.1
often show ID and dysmorphism due to unbalanced karyotype
Autosomal sex reversal
11p13 (including WT1 gene) associated with Wilms tumour, Frasier syndrome, Denys-Drash syndrome
Translocations involving 17q24.3-q25.1 (SOX9) associated with campomelic dysplasia (skeletal ab and early death)
X chromosome and sex reversal
XY female
duplication of Xp21 (DAX1) disrupts testis development
Hermaphroditism
-Gonads comprise both ovarian and testicular elements
Ambiguous external genitalia
Most commonly 46,XX
occasionally chimerism 46,XX/46,XY
-Ambiguous genitalia and gonads comprising:
Ovarian elements only = female pseudohermaphrodite
testicular elements only = male pseudohermaphrodite
