Sexual Differentiation & Disorders Flashcards
What is the difference between sexual determination and differentiation?
Sexual determination:
Genetically controlled process dependent on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female.
Sexual differentiation:
The process by which internal and external genitalia develop as male or female.
The two processes are contiguous and consist of several stages.
How is gonadal sex determined?
SRY gene creates the testis.
Sex determining region Y (SRY) switches on briefly during embryo development (>week 7) to make the gonad into a testis.
In its absence an ovary is formed.
Testis develops cells that make 2 important hormones which are anti-Mullerian hormone (AMH) and testosterone.
Products of the testis influence further gonadal and phenotypic sexual development.
How are the gonads developed after gonadal determination?
After fertilisation a pair of gonads develop which are bipotential.
Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3½ - 4½ weeks) on posterior wall of lower thoracic lumbar region.
The Wolffian duct would develop into the internal male genitalia and the Mullerian into the female
What three waves of cells invade the genital ridge?
- Primordial Germ Cells – become Sperm (male) or Oocytes (female).
- Primitive Sex Cords – become Sertoli cells (male) or Granulosa cells (female) come from the same origin and surround the sperm and oocytes.
- Mesonephric Cells – become blood vessels and Leydig cells (male) or Theca cells (female).
- Primitive Sex Cords – become Sertoli cells (male) or Granulosa cells (female) come from the same origin and surround the sperm and oocytes.
What happens during primordial germ cell migration?
An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks.
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.
What happens during the primitive sex cord development?
Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords.
SRY is what indicates the differentiation into Sertoli cells
SO
Male:
- SRY expression
- Penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules.
- Eventually become Sertoli Cells which express AMH.
Female:
- No SRY
- Sex cords ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – precursor of ovarian follicle
- Eventually become Granulosa cells.
What effect do the mesonephric cells have on the genital ridge?
These originate in the mesonephric primordium which are just lateral to the genital ridges.
In males they act under the influence of pre-sertoli cells (which themselves express SRY) to form…
- Vascular tissue
- Leydig cells (synthesize testosterone under the influence of Sertoli cells, do not express SRY)
- Basement membrane – contributing to formation of seminiferous tubules and rete-testis
In females without the influence of SRY they form…
- Vascular tissue
- Theca cells
What are the internal reproductive ducts depending on gender?
Mullerian ducts
- most important in female
- inhibited in the male by AMH (anti-Mullerian hormone)
Wolffian ducts
- most important in the male stimulated by testosterone
- lack of stimulation by testosterone means regression in female
How do the different ducts develop during internal sexual differentiation?
In the male the Mullerian duct disappears through regression
The wolffian duct grows into the epididymis, the vas deferens to the seminal vesicles etc.
In females the Wolffian duct regresses and disappears and the Mullerian duct develops into the uterine tube, the uterus and part of the vagina
What is DHT and what role does it have in sexual differentiation?
Testosterone is converted in the genital skin to the more potent androgen DHT (dihydrotestosterone) by 5-a-reductase.
DHT binds to the testosterone receptor, but is more potent than testosterone.
DHT causes differentiation of the male external genitalia:
- Clitoral area enlarges into penis
- Labia fuse and become ruggated to form scrotum
- Prostate forms
Name some disorders of sexual differentiation?
Gonadal dysgenesis - Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads.
Sex reversal - Phenotype does not match genotype, ie may be male genotypically but externally look like a female.
Intersex - Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.
Patients prefer to be known as someone with a ‘disorder of sexual differentiation’ or DSD.
Terms such as ‘pseudohermaphrodite’ and, ‘testicular feminisation’ are now obsolete.
What is androgen insensitivity syndrome?
What happens if in an XY individual... Testosterone is made but has no effect. Androgen insensitivity syndrome (AIS) Testes form and make AMH so Mullerian ducts regress. No differentiation of Wolffian ducts No external male genitalia
What are the different types of AIS and how are they diagnosed?
Complete AIS - incidence 1:20,000
- Appear completely female at birth and assigned female gender despite being XY.
- Have undescended testes.
Diagnosis?
- Usually present with primary amenorrhoea. Lack of body hair is a clue.
- Ultrasound scan and karyotype with male levels of androgens.
- Never responded to androgen so appear and often feel female.
Partial AIS - incidence unknown as is probably a spectrum
- Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris.
- Surgery was universal but now fortunately considered optional or at least best delayed. Decisions made on potential. Very difficult for parents.
What is 5-α-reductase deficiency?
What happens if in an XY individual…
Testosterone is made but not DHT?
5-α-reductase deficiency
Testes form and make AMH so Mullerian ducts regress.
Wolffian ducts develop
No external male genitals. Feminine or ambiguous genitalia
What happens to people with 5-α-reductase?
Incidence varies enormously as autosomal recessive and can depend on inter-related marriage.
Testes form, AMH acts, testosterone acts.
Internal structures form.
External structures do not develop.
May appear mainly female or may have ambiguous genitalia
The degree of the enzyme block varies and so therefore does the presentation.
What happens at puberty?
- Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.
