Disorders of sexual development Flashcards
What investigations can we do in order to evaluate a new born
- ) Genetics:
- karyotype
- FISH
- Molecular studies - ) Internal structures:
- Ultrasound
- Laparotomy - ) External genitalia
- Masculinisation score - ) Biochemistry
- Androgens
- Steroids
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
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
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
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
What are the different disorders of ovarian development?
- Ovotesticular DSD
- Testicular DSD
- Gonadal dysgenesis
What are the different disorders of androgen excess?
- Fetal
- Fetoplacental
- Maternal
Outline fetal androgen excess
- Congenital adrenal hyperplasia
- Exposure to adrenal androgens in utero
- Mullerian structures develop
- External genitalia are virilised
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
What is 21-hydroxylase
- steroid enzyme
- a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol
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
Explain fetoplacental androgen excess
- ) Aromatase deficiency
- Converts androgens to oestrogens
- High levels pf amdrogens can lead to virilisation of XX fetus
- Can lead to maternal virilisation in pregnancy - ) 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
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
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
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
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
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
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
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
Outline mild AIS
- external genitalia typically male
- May develop gynaecomastia necessating surgery
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
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
