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Flashcards in Disorders of sexual development Deck (22)
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1

What investigations can we do in order to evaluate a new born

1.) Genetics:
-karyotype
-FISH
-Molecular studies
2.) Internal structures:
-Ultrasound
-Laparotomy
3.) External genitalia
-Masculinisation score
4.) Biochemistry
-Androgens
-Steroids

2

What is ovotesticular disorder?

-Ovarian and testicular tissue in the same individual
-The presence of structures derived from the Mullerian ducts will depend on production of AMH
-The presence of structures derived from the Wolffian ducts& the degree of virilisation will depend on the production of testosterone

3

What are the different types of ovotesticular disorder?

-46,XX DSD can be caused by mosaic or chimeric forms of SRY+
-46, XY DSD can be caused by variants in SRY
-Sex chromosome DSD mosaic/chimera

4

Outline 46,XX Testicular DSD

-Low testosterone requires replacement, growth hormone treatment or mammoplasty may also be offered
-Most individuals are SRY+, rearrangements around
SOX9 and SOX3 have also been reported
-A minority of individuals present at birth with ambiguous genitalia
-The majority of individuals present after puberty with gynaecomastia, small tests& infertility

5

Outline 46 XX gonadal dysgenesis

-Failure of ovarian development
-Internal organs derived from Mullerian structures
-Female external genitalia
-Presents with delayed puberty, primary/secondary amenorrhea

6

What are the different disorders of ovarian development?

-Ovotesticular DSD
-Testicular DSD
-Gonadal dysgenesis

7

What are the different disorders of androgen excess?

-Fetal
-Fetoplacental
-Maternal

8

Outline fetal androgen excess

-Congenital adrenal hyperplasia
-Exposure to adrenal androgens in utero
-Mullerian structures develop
-External genitalia are virilised

9

What are the characteristics of congenital adrenal hyperplasia?

-Most common form is 21-hydroxylase deficiency
1.)-'classic form'= virilisation at birth, may also have salt wasting which is a life-threatening emergency
2.)Non- classic form' presents postnatally, may present at puberty with acne, hirsutism & irregular periods
-Treated with glucocorticoid/mineralocorticoid replacement
-surgery may be considered for virilisation
-May need treatment to delay puberty
-Fertility can be usually preserved

10

What is 21-hydroxylase

-steroid enzyme
- a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol

11

How can maternal androgen excess be caused?

-Luteoma- benign tumour of the ovary which can produce androgens& with virilising consequences for the fetus & mother
-exogenous androgens

12

Explain fetoplacental androgen excess

1.) Aromatase deficiency
-Converts androgens to oestrogens
-High levels pf amdrogens can lead to virilisation of XX fetus
-Can lead to maternal virilisation in pregnancy
2.) Cytochrome P450 oxidoreductase deficiency
-.Electron donor in steroidogenesis
-Broad range of phenotypes with different variants
-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

13

What are the characteristics of 46,XY, complete gonadal dysgenesis ?

-Dysgenetic testes
- Very low testosterone
-Internal organs derived from Mullerian structures
-Female external genitalia
-Presents with delayed puberty/primary amenorrhea
-Variants in SRY/MAP3K1 account for a significant proportion

14

What are the characteristics of 46,XY,partial gonadal dysgenesis

-Abnormal development of the testes
-Low testosterone
-may/may not have Mullerian structures
-Ambiguous external genitalia
-Variants in NR5A1/MAP3K1 account for a significant proportion

15

Outline gonadal regression

-Complete regression of testicular tissue on one or both sides
-Abnormal dysgenetic testes
-Degree of masculinisation reflects duration of testicular function prior to regression

16

Outline how disorders of androgen action come about

-AR is a nuclear receptor which mediates the effects of the androgens
-Level of receptor function determines phenotype
-Appearance of external genitalia, pubertal progression & fertility can be affected

17

What is complete AIS

-Testes& adrenal glands produce normal or increased levels of androgens
-Absent or rudimentary Mullerian structures
-Absent or rudimentary Wolffian structures
-External genitalia female but with short vagina
-Present in childhood with masses in the inguinal canals or at puberty with amenorrhea and scant pubic & axillary hair
-The testes are dormant till 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
-Normal breast development
-Scant pubic and axillary hair
-Primary amenorrhea

18

How can AIS be managed?

-Surgery/vaginal dilation may be considered after puberty
-Gonads have a cancer risk~5%
-Some individuals have gonads removed, generally after puberty, many women report a reduction in libido & loss of sense of well being
-Hormones replacement after gonadectomy- reproductive, bone, cardiovascular benefits
-Some individuals opt to retain the testes so that they don't have to take hormones and in the hope of advances enabling fertility

19

Outline partial AIS

-external genitalia typically female, male or ambiguous'--May present at puberty with clitoromegaly or gynaecomastia
-May be a role for early gonadectomy & hormones supplementation in 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

20

Outline mild AIS

-external genitalia typically male
-May develop gynaecomastia necessating surgery

21

Outline disorders of androgen synthesis

-5 alpha reductase deficiency
-Internal genitalia male
-Variable appearance of external genitalia: female>ambiguous> predominantly male- small penis, hypospadias
-Substantial variation on gender identity outcomes
-During puberty increased androgen levels leads to virilisation
-If patient raised as a girl may need to consider gonadectomy prior to puberty

22

Outline sex chromosome DSD

Turner syndrome and variants
-suspected in females with short stature,lymphedema, cardiac or renal abnormalities,absent or delayed puberty, premature ovarian failure and infertility
Klinefelter syndrome and variants
-suspected in males with hypogonadism, small testes,
azoospermia and gynecomastia, normal or tall stature, speech delay, learning disorders, and behavioural problems.
Chimerism
-individuals with 46,XX/46,XY chimerism may present with external genitalia ranging from typical male to ambiguous to typical female
Mosaicism
-individuals with 45,X/46,XY present as male or female depending on the percentage of 45,X cells