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MBCHB3: Reproduction, Development and Ageing > Lecture 19: Sexual differentiation > Flashcards

Lecture 19: Sexual differentiation Flashcards

1
Q

What are the 3 levels of sexual differentiation?

A
  • Gonads
  • Internal genitalia
  • External genitalia
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2
Q

Describe the bipotential fetus relating time to levels of sexual differentiation;

A

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.

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3
Q

Describe the formation of the gonad:

A

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)

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4
Q

Describe sex determination of the gonad:

A

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)

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5
Q

What are the key cell types of the testis? and what do they do?

A

Leydig cells: Secrete testosterone in response to testosterone.

Sertoli cells:

  • Secrete inhibin in response to FSH.
  • Secrete AMH
  • Support cells

Germ cells: Seminiferous cords

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6
Q

What are the key cell types of the ovaries? and what do they do?

A

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

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7
Q

What determines the formation of internal genitalia?

A

Testis! -> Wolffian ducts

  • Testosterone (leydig cells)
  • AMH (Sertoli cells)

If no testis then no T or AMH thus mullerian duct forms

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8
Q

Describe the mullerian ducts:

A

The mullerian ducts form female internal genitalia

  • Follopian tubes
  • Uterus
  • Upper 1/3 vagina
  • AMH if present will cause them to regress.
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9
Q

Describe wolffian ducts:

A

The wolffian ducts form male internal genitalia

  • Epididymis
  • Vas deferens
  • Seminal vesicle
  • If T is present they will maintain, otherwise will regress
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10
Q

How does external female genitalia formed?

A

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
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11
Q

How can disorders of sexual differentiation phenotype be determined?

A
  • Karyotype
  • Ultrasound and palpation for gonads
  • Anatomy examined
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12
Q

What are the most common types of disorders of sexual differentiation?

A
  • Virilised female (virilised means androgen have acted)

- Undervirilised male

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13
Q

How may a virilised female present?

A
  • Karyotype XX
  • Ovaries present
  • Normal internal genitalia (Uterus present)

Virilisation (some degree)

  • Clitoromeagly
  • Labia fusion
  • If severe can look like male

Implies androgen exposure.

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14
Q

How may a female fetus be exposed to androgens and become verilised?

A

Fetal:
- Congenital adrenal hyperplasia

Maternal

  • Use of medications including oral contraceptive pill
  • Severe PCOS
  • Androgen secreting tumor
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15
Q

How may undervirilised males presented?

A
  • Testis present
  • Absent uterus
  • Karyotype XY
  • External genitalia undervirilised
  • > Some combination of small phallus, often with hypospadias, testes may be non-descended
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16
Q

Why may a male be undervirilised? and what may the causes be?

A

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
17
Q

How do you manage disorders of sexual differentiation?

A
  • 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.

18
Q

What is screening when it comes to babies?

A

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
19
Q

Whats the newborn screening program in NZ?

A

Blood spot collected at 48hrs of age for all babies

Tests for:

  • congenital hypothyroidism
  • CF
  • PKU
  • Congenital adrenal hyperplasia
20
Q

How does congenital hypothyroidism justify screening on its own?

A

1:2500 born with congenital hypothyroidism.

Without early treatment significant risk of intellectual disability

21
Q

What are the types of congenital hypothyroidism?

A

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
22
Q

What do thyroid hormones do?

A

Key metabolic hormone with receptors in many tissue types

23
Q

What does adult hypothyroidism lead to? and children?

A
  • Cold intolerance
  • Poor energy / somnolence
  • Constipation
  • Weight gain

In children, same as above but also severely impaired growth.

24
Q

What does untreated congenital hypothyroidism lead to?

A
  • Thyroid hormone is required for normal neurological development before age of two
  • Untreated CHT leads to marked intellectual, motor and growth retardation
25
Q

How may CHT present?

A
  • Slow, sleepy baby
  • Poor feeding
  • Jaundice
  • Constipation
  • Large fortanelle
  • Large tongue
  • Poor tone

Commonest preventible cause of intellectual disability

26
Q

What happens to T4, TSH in hypothyroidism?

A

T4 will be low and TSH will be very high

27
Q

How is CHT treated?

A

Thyroid hormone (thyroxine)

T4 levels normally stabilise within a week. Same IQ as siblings, very good screening program.

28
Q

What happens in congenital adrenal hyperplasia?

A
  • Leads to failure to produce one or more steroid hormones
  • Build up of metabolite hormones

ACTH drives this adrenal growth.
Loss/reduced enzyme function

29
Q

Whats the most common enzyme deficiency because of congenital adrenal hyperplasia?

A

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

30
Q

What are the key steroids in 21-hydroxylase deficiency:

A
  • 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
31
Q

What happens in hyperplastic adrenals due to high ACTH:

A
  • Virilisation due to high 17OHP
  • Lack of cortisol = Poor energy, hypoglyceamia
  • Lack of aldosterone = Salt wasting, potential for crisis around 10 days of age
32
Q

What happens to 17OHP in preterm?

A

Intermediate elevations are common and thus needs repeated screening

33
Q

How would females present with 21OH deficiency?

A 
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

34
Q

How do males present with 21OH deficiency?

A
  • 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.

35
Q

What are some examples of mild 21OH deficiency phenotypes:

A

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
36
Q

What are the goals treatment of 21 OHase deficiency treatment?

A
  • 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

37
Q

What are some other important issues of 21 OHase deficiency?

A

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

MBCHB3: Reproduction, Development and Ageing (24 decks)

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