Sexual Differentiation Flashcards
What is the difference between sexual determination and differentiation?
Sexual determination: genetically controlled process dependent on the Y chromosome ‘switch’. Once this male/fem determination has been made sexual differentiation starts.
Sexual differentiation: process by which internal and external genitalia develop as male or female.
What is the SRY gene?
The SRY gene on the p arm of the Y chromosome codes for SRY protein, a transcription factor that upregulates its own gene
Sex determining region Y (SRY) switches on briefly during >week 7 of development to make the gonad into a testis. In its absence an ovary is formed.
Describe the very first part of gonadal development, and explain the importance of genital ridges- what they are derived from, what do they develop into etc
After fertilisation, a pair of bipotential gonads develop
Image shows 3–4-week-old embryo, dotted line is a cross-section, which contains genital ridges.
Genital ridges: precursor is derived from mesenchymal tissue called genital ridge primordia. These develop on posterior lower thoracolumbar wall at ~3 ½ - 4 ½ weeks.
Rn embryo=bipotential; genital ridges can form testes or ovaries!
Which ducts determine ovary/testi development? What do they eventually form?
Mullerian duct: will eventually form the uterus, uterine tubes and the upper 2/3rds of the vagina if the embryo becomes female
Wolffian duct: will eventually form the vas deferens, seminal vesicles and prostate gland if the Mullerian duct does not develop
3 waves of cells invade the genital ridge…
What are these 3 cells?
Primordial germ cells: become spermatocytes (m) or oocytes (f)
Primitive sex cords: become Sertoli cells of the testis (m), or Granulosa cells of the ovary (f)
Mesonephric cells: become blood vessels and testosterone-producing Leydig cells in males, or Theca cells in females
Three waves of cells which invade the genital ridge include
primordial germ cells
primitive sex chords
mesonephric cells.
Describe primoridial germ cells in detail- what and where are they, how do the cells divide, where do they migrate to?
Primordial germ cells become spermatocytes (m) or oocytes (f)
They r a small cluster of cells in the yolk sac epithelium that expand by mitosis at around 3 weeks
Atp cells are diploid (not haploid like gametes)
They then migrate to the connective tissue of the hind gut, to the region of the developing kidney and on to the genital ridge – completed by 6 weeks
Three waves of cells which invade the genital ridge include
primordial germ cells
primitive sex chords
mesonephric cells.
Describe primitive sex cords in detail
Germinal epith cells overlying the genital ridge mesenchyme migrate inwards as columns called primitive sex cords
M: cells express SRY. They penetrate the medullary mesenchyme and surround primordial germ cells to form testis cords. Primitive sex cords then differentiate–> Sertoli cells, which express AMH
F: primitive sex cord cells don’t express SRY, ill-defined cords
They do not penetrate deeply, but condense in the cortex as clusters around primordial germ cells, like mature ovary follicles. Cells differentiate–> Granulosa cells
Three waves of cells which invade the genital ridge include
primordial germ cells
primitive sex chords
mesonephric cells.
Describe mesonephric cells in detail- where do they originate, what do they form in males vs females etc
Mesonephric cells originate in the mesonephric primordium, just lateral to the genital ridges
In males, under pre-Sertoli cells (which express SRY), they form:
vascular tissue
Leydig cells (make testosterone, don’t express SRY)
Basement membrane (forms seminiferous tubules + rete testis)
In females, w/o SRY the mesonephric cells form vascular tissue and Theca cells (make androstenedione only after puberty)
What are mullerian and wolfian ducts stimulated and inhibited by?
Wolffian (mesonephric) ducts: Stimulated by testosterone. Females dont have testosterone so Wolffian duct degenerates
Mullerian (paramesonephric) ducts: inhibited by AMH produced by Sertoli cells in the developing male
Describe external genitalia formation in males
Testosterone is converted to androgen DHT by 5a-reductase
DHT binds to testosterone receptor, but is 10x more potent than testosterone
DHT causes differentiation of male external genitalia:
Clitoral area (genital tubercle + urethral fold) enlarges –>penis
Labia (genital swellings) fuse and rugate to form scrotum
Prostate forms
note- 5a-reductase also in females but no testosterone–>DHT is not formed, foetus follows fem external genitalia pathway
What are some disorders of sexual differentiation?
Gonadal dysgenesis: incomplete sexual differentiation/abnormal gonadal development
Usually due to male missing SRY, or deletion of the 2nd X chromosome in females.
Intersex: Pts have components of both repro tracts, or ambiguous genitalia. Makes sex of an infant hard to determine
Sex reversal: phenotype doesn’t match genotype
note: pts prefer ‘disorder of sexual differentiation’ or DSD
Explain androgen insenstivity syndrome in gonadal dysgenesis
Androgen insensitivity syndrome (AIS): XY makes testosterone, but it has no effect
XY individual still makes SRY, so will develop testes
The testes contain Sertoli cells which produce AMH, leading to normal Mullerian duct regression
Leydig cells produce testosterone, though it has no effect.
So Wolffian ducts won’t grow–> lack of internal male genitalia (except testes)
Lack of testosterone limits 5Alpha-reductase activity–> limits DHT production, affecting external genitalia as well
What is the difference between complete and partial AIS? How do these patients present?
What is the incidence of complete AIS?
Complete AIS= aprox 1 in 20,000.
Appear completely female at birth despite being XY, undescended testes.
First present w primary amenorrhoea and no body hair (lack of testosterone). USS reveals undescended testes, bloods reveal male androgen levels, karyotypes reveal XY genotype. Since the pt has never responded to androgens, they appear and feel fem
Partial AIS: range from ambiguous genitalia to large clit/micropenis. Surgery was universal treatment but is now optional.
What happens if in an XY individual has 5-α-reductase deficiency?
In XY individual, SRY forms testes, which produce AMH from Sertoli cells, Mullerian ducts regress
The Leydig cells of the testes produce testosterone, causing Wolffian duct differentiation, so internal genitalia unaffected
BUT 5a-reductase deficiency stops DHT production–> external genitalia + prostate wont form, so fem/ambiguous external genitalia seen
How does presentation of 5-α-reductase deficiency differ?
The degree of enzyme block varies, so so does presentation
Incidence varies enormously as it’s an autosomal recessive condition, which can depend on inter-related marriage
At puberty, potential must be assessed bc high testosterone levels that occur at adrenarche (as less is converted to DHT) may induce virilisation
The normal process of the HPA axis is…
ACTH stimulates cholesterol uptake into adrenal cortex and also upregulates cholesterol side chain cleavage enzyme (P450scc), producing more progestogens
