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Stage 2: Human Deveopment > Disorders of Sexual Development > Flashcards

Disorders of Sexual Development Flashcards

1
Q

How can DSDs present at birth in females?

A

Ambiguous genitalia ranging from large clitoris to male genitalia

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2
Q

How can DSDs present in childhood in females?

A

Inguinal hernia

Labial masses which turn out to be testes

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3
Q

How can DSDs present at puberty in females?

A

Amenorrhea

Hirsutism (unwanted amounts of hair growth)

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4
Q

How can DSDs present at birth in males?

A

Ambiguous genitalia

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5
Q

How can DSDs present at puberty in males?

A

Reduced hair
Gynaecomastia (breast tissue)
Small testes
Cyclical haematuria

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6
Q

How can DSDs present as an adult in males?

A

Infertility if mildly affected

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7
Q

What investigations are done if DSD is suspected?

A

1) Genetics → karyotype, FISH, molecular studies
2) Internal structures → US, laparotomy
3) External genitalia → masculinisation score
4) Biochemistry → androgens, steroids

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8
Q

Describe the management options for DSD

A

1) Gonadectomy → cancer risks of not removing gonads unclear, impact on fertility
2) Surgery on external genitalia → may affect sexual function, scar tissue, nerve endings (sensation)
3) Hormone treatment → can often be delayed until puberty if gonads are left in until teenager can be involved

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9
Q

What are the disorders of ovarian development? (46,XX)

A

1) 46, XX testicular DSD

2) 46, XX gonadal dysgenesis

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10
Q

Describe 46, XX testicular DSD presentation

A
  • Minority present at birth with ambiguous genitalia (testes not fully formed)
  • Most present after puberty with gynaecomastia, small testes and infertility
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11
Q

Describe genetics of 46, XX testicular DSD

A
  • Most individuals are SRY+

- Rearrangements around SOX9 and SOX3

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12
Q

Describe treatment of 46, XX testicular DSD

A
  • Low testosterone requires replacement
  • GH treatment
  • Mammoplasty
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13
Q

Describe 46, XX gonadal dysgenesis

A
  • Failure of ovarian development (no functional ovary producing hormones)
  • Internal organs derived from Mullerian structures
  • Female external genitalia
  • Presents with delayed puberty, primary/secondary amenorrhea
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14
Q

What is the karyotype of disorders of androgen excess

A

46, XX

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15
Q

What is the disease of fetal androgen excess?

A

Congenital adrenal hyperplasia

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16
Q

Describe CAH

A
  • Mullerian structures develop (internal structures are female)
  • Excess androgen due to production of androgen in adrenal gland so tissues sensitive to androgen that form external genitalia are exposed to androgen so external genitalia are male in utero
  • External genitalia are virilised
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17
Q

What is the most common form of CAH?

A

21-hydroxylase deficiency

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18
Q

Why does 21-hydroxylase deficiency lead to CAH?

A

Less product (i.e. cortisol and aldosterone) so build up of precursors which are diverted down other pathway to form androgens

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19
Q

What is the classic presentation of CAH?

A

Virilisation at birth

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20
Q

What is the life-threatening emergency of CAH?

A

Salt wasting → child cant produce enough cortisol or aldosterone so cant maintain fluid homeostasis, need fluid and hormone replacement

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21
Q

What is the non-classic presentation of CAH?

A

May present at puberty with acne, hirsutism and irregular periods

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22
Q

What is the treatment for CAH?

A

1) Glucocorticoid/mineralocorticoid replacement
2) Surgery may be considered for virilisation depending on extent of male genitalia
3) May need treatment to delay puberty

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23
Q

How is fertility affected in CAH?

A

Usually preserved bc have ovaries and uterus

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24
Q

What are two causes of fetoplacental androgen excess?

A

1) Aromatase deficiency

2) Cytochrome P450 oxidoreductase deficiency

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25
Q

Describe aromatase deficiency

A
  • Converts androgens to oestrogens (other way round?)
  • High levels of androgens can lead to virilisation of XX fetus
  • Can lead to maternal virilisation in pregnancy
26
Q

Describe cytochrome P450 oxidoreductase deficiency

A
  • Electron donor in steroidogenesis
  • Broad range of phenotypes with different variants (moderate deficiency = virilisation)
  • High levels of androgens in an affected fetus can lead to virilisation of XX fetus
  • Can lead to maternal virilisation
  • Can also lead to XY DSD
27
Q

What is the cause of maternal androgen excess?

A

Luteoma

28
Q

What is a luteoma?

A

Benign tumour of the ovary which can produce (exogenous) androgens with virilising consequences for the fetus and mother

29
Q

What are the 3 types of disorders of testicular development (46,XY DSD)?

A

1) 46,XY complete gonadal dysgenesis
2) 46,XY partial gonadal dysgenesis
3) Gonadal regression

30
Q

Describe pathology of 46,XY complete gonadal dysgenesis

A
  • Dysgenic testes (testes don’t really form)
  • V low testosterone and AMH
  • Internal organs derived from Mullerian structures due to low AMH
31
Q

Describe presentation of 46,XY complete gonadal dysgenesis

A
  • Female external genitalia

- Presents with delayed puberty/primary amenorrhoea

32
Q

Describe genetics of 46,XY complete gonadal dysgenesis

A

Variants in SRY/MAP3K1 account for significant proportion

33
Q

Describe pathology of 46,XY partial gonadal dysgenesis

A
  • Abnormal development of testes
  • Low testosterone and AMH
  • ± Mullerian structures (depends on amount of hormone produced)
34
Q

Describe presentation of 46,XY partial gonadal dysgenesis

A

Ambiguous external genitalia depending on amount of hormone produced

35
Q

Describe genetics of 46,XY partial gonadal dysgenesis

A

Variants in NR5A1/MAP3K1 account for significant proportion

36
Q

Describe gonadal regression

A
  • Complete regression of testicular tissue on one or both sides
  • Abnormal dysgenic testes
  • Degree of masculinisation reflects/depends on duration of testicular function prior to regression
37
Q

What are 4 examples of disorders of androgen synthesis or action?

A

1) AIS (androgen (testosterone) insensitivity syndrome)
2) LH receptor defects
3) AMH defects
4) 5 alpha reductase deficiency

38
Q

Is AIS a disorder of androgen action or synthesis?

A

Action

39
Q

What is the karyotype of disorders of androgen synthesis or action?

A

46, XY

40
Q

What is the androgen receptor?

A

A nuclear receptor which mediates the effects of androgens

41
Q

What determines the phenotype of AIS?

A

Level of receptor function

42
Q

What can be affected by AIS?

A

Appearance of external genitalia
Pubertal progression
Fertility

43
Q

Describe pathology of AIS

A

The body can’t respond to testosterone produced by testes, so external genitalia doesn’t form properly and Wolffian structures aren’t stabilised

44
Q

Describe complete AIS

A
  • Testes and adrenal glands produce normal or increased levels of androgens (testosterone)
  • Testes are dormant until puberty when they are stimulated to enlarge and gradually increase androgen production to adult levels
  • Testosterone is aromatised to oestrogen so go into puberty spontaneously
45
Q

How does AIS present?

A
  • Absent or rudimentary Mullerian or Wolffian structures
  • External genitalia female but with a short vagina and no uterus/ovaries
  • Present in childhood with masses in the inguinal canals (testes) or at puberty with primary amenorrhea and scant pubic and axillary hair
  • Normal breast development
46
Q

Although most women present with AIS after puberty why could they present at childhood?

A

Inguinal hernias

Testes have slightly descended

47
Q

Describe gonadectomy for complete AIS

A
  • Many women with complete AIS will decide to leave the testes bc at puberty they start producing testosterone of which some is aromatised to oestrogen meaning they can go through puberty relatively normally without having to take lots of hormones
  • After puberty, recommended to remove testes bc of cancer risk
48
Q

What are treatment options for complete AIS?

A

1) Surgery/vaginal dilation after puberty to improve function
2) Gland removal after puberty but many women report reduction in libido and loss of sense of well being
3) Hormone replacement after gonadectomy (reproductive, bone and CV benefits)

49
Q

Why may some individuals with complete AIS opt to retain their testes?

A

Do not have to take hormones

Hope of advances in reproductive technology enabling fertility

50
Q

What is the vagina present but short in complete AIS?

A

Top third of the vagina is contributed by Mullerian structures which are degenerated in these women

51
Q

What is the cancer risk of gonads in complete AIS?

A

5%

52
Q

Describe partial AIS

A
  • Androgen receptor works to an extent, depends on mutation
  • External genitalia can be anything
  • May present at puberty with clitoromegaly or gynaecomastia
  • Uncertain effect of prenatal androgen exposure on the brain → not as simple to manage
53
Q

Describe treatment for partial AIS

A
  • May be a role for early gonadectomy and hormone supplementation in the individuals raised as females → puberty can be delayed by administration of GnRH agonists
  • May be a role for orchidopexy or hypospadias repair and androgen treatment from puberty in individuals raised as males
54
Q

Describe mild AIS

A
  • Androgen receptor is working slightly less than might expect
  • External genitalia are typically male
  • Often childhood and adolescence is normal
  • May develop gynaecomastia necessitating surgery
  • Often comes to light as part of investigations for infertility
55
Q

What is the role of 5 alpha reductase?

A

Converts testosterone to DHT (more potent form of testosterone which drives the effects on tissue of external genitalia to form male phenotype)

56
Q

Describe 5 alpha reductase deficiency?

A
  • Internal genitalia male
  • Variable appearance of genitalia depending on mutation
  • Substantial variation in gender identity
  • During puberty, increased androgen levels lead to virilisation (can be reason for presentation)
  • If patient raised as a girl may need to consider gonadectomy prior to puberty to prevent surge in androgen at puberty
57
Q

What is another form of DSD?

A

Sex chromosome

58
Q

What are features of Turner syndrome (45,X)?

A 
Females with...
Short stature 
Lymphedema 
Cardiac or renal abnormalities 
Absent or delayed puberty 
Premature ovarian failure 
Infertility
59
Q

What are features of Klinefelter syndrome (47,XXY)?

A 
Males with...
Hypogonadism 
Small testes
Azoospermia and gynaecomastia 
Normal or tall stature 
Speech delay 
Learning disorders 
Behavioural problems
60
Q

Describe sex chromosome chimerism

A
  • Individuals with 46,XX/46,XY chimerism may be present with external genitalia ranging from typical male to ambiguous to typical female
  • Two different cell lines in the body, one of them has a different complement of sex chromosomes to the other one → DSD
61
Q

Describe sex chromosome mosaicism

A
  • Individuals with 45,X/46,XY present as male or female depending on the percentage of 45,X cells

Stage 2: Human Deveopment (34 decks)

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