Lecture 19: Sexual differentiation Flashcards
What are the 3 levels of sexual differentiation?
- Gonads
- Internal genitalia
- External genitalia
Describe the bipotential fetus relating time to levels of sexual differentiation;
Bipotential gonads: <6 weeks
Bipotential internal genitalia: <7 weeks
Bipotential external genitalia: <8 weeks
The early fetus has the potential to develop into male or female sex depending on the expression of certain genes/transcription factors and the action of certain hormones.
Describe the formation of the gonad:
Paired genital ridges form in the intermediate mesoderm of developing embryo
Three parts:
- Pronephros (caudal = adrenals)
- Mesonephros : Central part = gonads and internal genitalia i.e wolffian and mullerian ducts
- Metanephros : (Posterior end forms kidneys)
Germ cells migrate in from yolk sac (depend on genes and factors, mutations can effect development)
Describe sex determination of the gonad:
Y chromosome contains SRY gene -> Sex determining Region of Y chromosome.
No SRY = no testis, and ovaries form instead. (its presence determines which transcription factors are activated etc)
What are the key cell types of the testis? and what do they do?
Leydig cells: Secrete testosterone in response to testosterone.
Sertoli cells:
- Secrete inhibin in response to FSH.
- Secrete AMH
- Support cells
Germ cells: Seminiferous cords
What are the key cell types of the ovaries? and what do they do?
Thecal cells:
- Secrete T that is converted to estrogen by the GCs
Granulosa cells
- Support cells in ovarian follicles, convert T to E2
Germ cells - Oocytes
- The fetus produces all her oocytes in fetal life, which enter a state of meiotic arrest until pubertal cycling begins
What determines the formation of internal genitalia?
Testis! -> Wolffian ducts
- Testosterone (leydig cells)
- AMH (Sertoli cells)
If no testis then no T or AMH thus mullerian duct forms
Describe the mullerian ducts:
The mullerian ducts form female internal genitalia
- Follopian tubes
- Uterus
- Upper 1/3 vagina
- AMH if present will cause them to regress.
Describe wolffian ducts:
The wolffian ducts form male internal genitalia
- Epididymis
- Vas deferens
- Seminal vesicle
- If T is present they will maintain, otherwise will regress
How does external female genitalia formed?
The bipotential fetus can develop male or female genitalia depending on the presence or absence of high conc. of androgens (particularly DHT)
- > If testis is present, male external genitalia should form: Scrotum, penis with urethral meatus at the tip of the glans
- > If no testis, female genitalia should form: Labia, vagina, with a small clitoris
How can disorders of sexual differentiation phenotype be determined?
- Karyotype
- Ultrasound and palpation for gonads
- Anatomy examined
What are the most common types of disorders of sexual differentiation?
- Virilised female (virilised means androgen have acted)
- Undervirilised male
How may a virilised female present?
- Karyotype XX
- Ovaries present
- Normal internal genitalia (Uterus present)
Virilisation (some degree)
- Clitoromeagly
- Labia fusion
- If severe can look like male
Implies androgen exposure.
How may a female fetus be exposed to androgens and become verilised?
Fetal:
- Congenital adrenal hyperplasia
Maternal
- Use of medications including oral contraceptive pill
- Severe PCOS
- Androgen secreting tumor
How may undervirilised males presented?
- Testis present
- Absent uterus
- Karyotype XY
- External genitalia undervirilised
- > Some combination of small phallus, often with hypospadias, testes may be non-descended
Why may a male be undervirilised? and what may the causes be?
Implies lack of prenatal androgen exposure or inability to respond to testosterone.
Fetal causes:
- LH receptor mutation
- Steroid biosynthetic defect (cannot make t or DHT)
- Androgen receptor mutation
How do you manage disorders of sexual differentiation?
- Determining underlying diagnosis (can be fatal)
- Management of family and child focussed decision making is critical. i.e Paediatric endocrinologists, paediatric surgeons, child psychologists/psychiatrists.
Surgery to correct is often deferred to see what child wants.
What is screening when it comes to babies?
Screening sorts those who might have a condition from those who probably dont have it.
- Must be followed by diagnositc tests (if positive screen)
- Dont always find all cases
Whats the newborn screening program in NZ?
Blood spot collected at 48hrs of age for all babies
Tests for:
- congenital hypothyroidism
- CF
- PKU
- Congenital adrenal hyperplasia
How does congenital hypothyroidism justify screening on its own?
1:2500 born with congenital hypothyroidism.
Without early treatment significant risk of intellectual disability
What are the types of congenital hypothyroidism?
Thyroid malformation
- Congenital athyreosis (no thyroid gland)
- Ectopic thyroid (near base of tongue)
- Sporadic
Thyroid dyshormonogenesis
- T4 cant be made sufficiently b/c metabolic dysf.
- Autosomal recessive genetic inheritance
What do thyroid hormones do?
Key metabolic hormone with receptors in many tissue types
What does adult hypothyroidism lead to? and children?
- Cold intolerance
- Poor energy / somnolence
- Constipation
- Weight gain
In children, same as above but also severely impaired growth.
What does untreated congenital hypothyroidism lead to?
- Thyroid hormone is required for normal neurological development before age of two
- Untreated CHT leads to marked intellectual, motor and growth retardation
How may CHT present?
- Slow, sleepy baby
- Poor feeding
- Jaundice
- Constipation
- Large fortanelle
- Large tongue
- Poor tone
Commonest preventible cause of intellectual disability
What happens to T4, TSH in hypothyroidism?
T4 will be low and TSH will be very high
How is CHT treated?
Thyroid hormone (thyroxine)
T4 levels normally stabilise within a week. Same IQ as siblings, very good screening program.
What happens in congenital adrenal hyperplasia?
- Leads to failure to produce one or more steroid hormones
- Build up of metabolite hormones
ACTH drives this adrenal growth.
Loss/reduced enzyme function
Whats the most common enzyme deficiency because of congenital adrenal hyperplasia?
21 hydroxylase deficiency
Causes salt-wasting crisis and risk of death. Impairs the ability to produce aldosterone and cortisol and leads to build up of 17-hydroxy-progesterone
What are the key steroids in 21-hydroxylase deficiency:
- Aldosterone is necessary for regulation of extra-cellular fluid volume and retention of sodium / excretion of potassium
- Cortisol is necessary to maintain normal blood sugar, to ensure normal responses to catecholamines, and as a stress hormone
- 17-OHP is a weak androgen, as it gets converted to T and DHT
What happens in hyperplastic adrenals due to high ACTH:
- Virilisation due to high 17OHP
- Lack of cortisol = Poor energy, hypoglyceamia
- Lack of aldosterone = Salt wasting, potential for crisis around 10 days of age
What happens to 17OHP in preterm?
Intermediate elevations are common and thus needs repeated screening
How would females present with 21OH deficiency?
Ambiguous genetalia Virilised XX - Clitoromeagly - Labial fusion - Can appear as male - No testes palpable (b/c none) - Normal uterus present
Girls identified early thus treated before severe illness
How do males present with 21OH deficiency?
- Extra androgen has no important effects, normal appearance
- But they slowly waste salt, lose weight, become shocked
- Hyponatraemic and hyperkalaemic
- Hypoglyceamic
Real risk fo dying ~10-15 days.
What are some examples of mild 21OH deficiency phenotypes:
Differ in terms of how active the 21OHase enzyme is
Simple virilising
- Make just enough aldosterone to get by
- Do no salt waste
- Girls present virilised
- boys present in early childhood with signs of virilisation such as pubic hair and genital growth
Non-classical CAH
- Present as mild androgenic effects in girls
- PCOS like picture after puberty
- Early onset of pubic hair, acne, body odour
What are the goals treatment of 21 OHase deficiency treatment?
- Replace glucocorticoid (Cortisol)
- Replace mineralcorticoid (aldosterone)
Suppress ACTH, so that 17OHP is not produced.
Give excess glucocorticoid in order to suppress ACTH (Hydrocortisone).
Fludrocortisone to replace mineralcorticoid.
Infants also require salt supplements b/c resistant to fludrocortisone.
In times of stress must give higher doses of hydrocortisone. i.e infection with fever, broken bone, general anaesthetic
What are some other important issues of 21 OHase deficiency?
Growth monitoring - Undertreatment :17OHP accelerates growth, but also leads to premature stop growth (not reaching genetic potential) (overtreatment with glucocorticoids impairs growth diretly)
Gender:
- Usually raised in concordance with genetic sex
- Evidence for severely virilised girls stick with whatever gender they are raised
Ambiguous genitalia (girls)
- Medical treatment leads to some reduction in clitoromeagly
- Often offered clitoral reduction surgery
