Sexual differentiation and disorders (repro) Flashcards
Sexual determination
Genetically controlled process dependant 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.
Similarities
The 2 processes are contiguous and consist of several stages
Gonadal sex
- 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.
Gonadal development
- After fertilisation, a pair of gonads develop which are biopotential.
- Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3.5-4.5 weeks) on posterior wall of lower thoracic lumbar region.
Genital ridge
3 waves of cells invade the genital ridge
1) Primordial Germ cells - become sperm (male) or oocytes (female)
2) Primitive sex cords - become Sertoli cells (male) or Granulosa cells (female)
3) Mesonephric cells - become blood vessels and Leydig cells (male) or Theca cells (female)
1) Primordial germ cell migration
- An initially small cluster of cells in the epithelium of the yolk. sac which 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
2) Primitive sex cords
- Cells from the germinal epithelium, overlying the genital ridge mesenchyme that migrate inwards as columns called the primitive sex cords
Primitive sex cords (Sertoli)
Male:
- SRY expression
- penetrate medullary mesenchyme and surround primordial germ cells to form testis cords (precursor of seminiferous tubules)
- eventually become Sertoli cells which express AMH
Primitive sex cords (Granulosa)
Female:
- No SRY expression
- 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
3) Mesonephric cells
- Originate in the mesonephric primordium which are just lateral to the genital ridges
Mesonephric cells in males
Act under the influence of pre-sertoli cells (express SRY) to form:
- vascular tissue
- Leydig cells (synthesise testosterone, do not express STY)
- Basement membrane (contributing formation of seminiferous tubules and rete-testis
Mesonephric cells in females
Without the influence of SRY they form:
- vascular tissue
- Theca cells
Gonadal sex summary (males)
Invading cells:
- Primordial germ cells = Spermatozoa (sperm)
- Primitive sex cords = Sertoli cells (SRY, AMH)
- Mesonephric cells = Leydig cells (Androgens)
Gonadal sex summary (females)
Invading cells:
- Primordial germ cells = Oocytes
- Primitive sex cords = Granulosa cells
- Mesophrenic cells = Theca cells
Mullerian ducts
- most important in female
- inhibited in the male by AMH
Wolffian ducts
- most important in the male stimulated by testosterone
Internal sexual differentiation (male)
- Epididymis
- Testis
- Vas deferens.
- Urinary bladder
- Seminal vesicle
- Prostate gland
Internal sexual differentiation (female)
- Ovary
- Oviduct
- Degenerating Wolffian duct
- Uterus
- Urinary bladder
- Vagina
5-alpha-reductase & DHT
- Testosterone converted in the genital skin to androgen DHT (dihydrotestosterone) by 5-alpha-reductase
- DHT binds to testosterone receptor. and is more potent
External differentiation by DHT
DHT causes differentiation of the male external genitalia:
- clitorial area enlarges into penis
- Labia fuse and become ruggated to form scrotum
- Prostate forms
Sex differentiation. summary (male)
- Undifferentiated gonad develops into Testis due to SRY
- AMH produced by Sertoli cells (regression of mullein ducts)
- Testosterone produced by Leydig cells (differentiation and growth of wolffian duct structures seminal vesicles and vas deferens)
- DHT produced by testosterone in the genital skin (fusion of labial scrotal folds growth of phallus and prostate)
Sex differentiation summary (female)
- Undifferentiated gonad develops. into ovary due to lack of SRY
- Mullerian ducts differentiate and grow into uterine tubes, uterus and upper 1/3 of vagina
- Regression of Wolffian ducts due to lack of androgens
- Lack of androgen leads to vagina, labia. and clitoris
Disorders of sexual differentiation
Gonadal dysgenesis (4 types) - sexual differentiation is incomplete. Usually missing SRY in male, or partial or. complete deletion of second X in female. Used as a general description of abnormal development of 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 with a ‘ disorder of sexual. differentiation’ or DSD
- ‘Pseudohermaphrodite’ and ‘testicular feminisation’ are obsolete
Androgen insensitivity syndrome (AIS)
- An XY makes testosterone but it has no effect
- Testes form and make AMH so Mullerian ducts regress
- Testosterone doesn’t act so no differentiation of Wolffian ducts
- No DHT forms so no external male genitalia
Complete AIS: - Incidence 1 in 20,000
- Appear completely female at birth despite being XY
- Undescended testes
- Usually present with primary amenorrhea and lack of body hair
- Ultrasound shows internal genitalia
- Karyotype with male levels of androgens
- Doesn’t respond to androgens so appears and often feels female
Partial AIS: - incidence unknown as its 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 delayed. Decisions made on potential, very difficult for parents
5-alpha-reductase deficiency
- An XY produces testosterone and acts on it but doesn’t produce DHT
- Testes form and AMH is made so Mullerian ducts regress
- Testosterone allows Wolffian ducts to develop
- Lack of DHT results in no external male genitals
- Incidence varies enormously as autosomal recessive and can depend on inter-related marriage
- All 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
- Need to assess potential as high testosterone level, will occur at adrenarche and puberty may induce virilisation
Turner syndrome
- XO as only have 1 out of 2 X chromsomes
- Failure of ovarian function
- Incidence 1 in 3,000
- ‘Streak’ ovaries
- Uterus and tubes are present but small
- Other defects in growth and development
- May be fertile
- Many have mosaicism
- Hormone support of bones and uterus
Congenital adrenal hyperplasia
- An XX is exposed to high levels of androgens in utero
- No SRY so no testes and no AMH
- Mullerian ducts remain
- Masculinised external genitalia.
- Androgen levels usually not high enough to fully rescue Wolffian ducts
- Incidence 1 in 15,000
- Completeness of. the block varies
- If enzyme absent then children may be wrongly gender. assigned at birth or may have ambiguous genitalia
- possibility of salt wasting due to lack of aldosterone which can be lethal
- Often require treatment with. glucocorticoids to correct feedback
Hypothalamic Pituitary Adrenal Axis
- The PVN in the hypothalamus releases Corticotropin releasing hormone (CRH) into the pituitary gland
- Stimulates pituitary gland to secrete Adrenocorticotropic hormone (ACTH)
- ACTH stimulates rapid uptake of cholesterol into the adrenal cortex
- This upregulates cholesterol side-chain cleavage enzyme (P450scc)
- This stimulates glucocorticoid (cortisol) secretion
Conclusion
- Correct sexual differentiation requires genetic, anatomical and endocrine components
- Disorders are rare, but have allowed scientists to understand the requirements for normal development
- Diagnosis and treatment of conditions of abnormal sexual differentiation requires a specialist team
- Long term functioning of the person is now the primary issue rather than immediate ‘corrective’ surgery
Glossery
- Mullerian duct – embryonic ducts developing into female internal internal genitalia
- Wolffian duct - embryonic ducts developing into male internal internal genitalia
- Sex determining region Y (SRY) – important transcription factor on Y chromosome
- Primordial germ cell – cells that develop into sperm or oocytes
- Primitive sex cords – cells that develop into gonadal cells associated with germ cells
- Mesonephric cells - cells that develop into gonadal cells that produce androgens
- 5-alpha reductase – enzyme involved in development of male external genitalia
- Gonadal dysgenesis – sexual differentiation is incomplete, usually abnormal development of gonads
- Sex reversal – phenotype does not match genotype
Intersex – some components of both male and female or ambiguous genitalia
