Disorders of sexual differentiation Flashcards
What are the 3 ways we can classify Disorders of sexual differentiation
Gonadal dysgenesis - Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads.
Sex reversal - Phenotype does not match genotype, ie may be male genotypically but externally look like a female.
Intersex - Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.
Describe Androgen Insensitivity Syndrome
XY individual Testosterone is made but has no effect Testes form and make AMH so Mullerian ducts regress. No differentiation of Wolffian ducts No external male genitalia
Features of Complete AIS
Undescended testes.
No uterus or fallopian tubes
External genitalia appear female - abbreviated blind vaginal pouch.
Usually present with primary amenorrhoea. Lack of body hair is a clue.
Ultrasound scan and karyotype with male levels of androgens.
Hormonal puberty may be feminizing without intervention due to aromatization of endogenous androgens to estrogens. Lacking response to androgen.
Sex assignment and rearing almost always female.
Differentiation of gender role and identity usually feminine. In adulthood, sexuality often conforms to typical heterosexual female expectations
Features of Partial AIS
Spectrum of phenotypes including almost normal female external genitalia through ambiguous genitalia (perineoscrotal hypospadias, microphallus, cryptorchidism).
Minor genital deviations go unnoticed or may be surgically repaired.
At puberty development of male secondary characteristics may not be very pronounced. In some cases pubertal gynecomastia (androgen/estrogen ratio) or ambiguous genitalia surgically corrected. Androgen therapy in some cases.
Majority of individuals develop an identity commensurate with their assigned gender - around 20% desire to change gender usually in adolescence or adulthood.
Describe Persistent Mullerian Duct syndrome
Patient doesn’t respond to AMH
PMDS type I results from mutations of the gene for AMH on chromosome 19.
PMDS type II results from mutations of the gene for the AMH receptor (AMH-RII) on chromosome 12.
Both autosomal recessive conditions with expression usually limited to XY offspring.
Testes form and either fail to make AMH or AMH receptor absent.
Mullerian ducts remain.
Differentiation of Wolffian ducts and masculinised external genitalia
Persistent mullerian duct syndrome clinical features
60–70% of cases have intra-abdominal Mullerian structures and testes in a position simulating that of the ovaries
20–30% have one testis in a hernial sac or scrotum together with Mullerian structures.
10% have both testes located in the same hernial sac (transverse testicular ectopia) along with the uterine tubes and/or uterine structures.
All have increased risk of malignant transformation.
Treatments for persistent mullerian duct syndrome
Surgery (orchiopexy) to retrieve the testes and position them in the scrotum. If testes cannot be retrieved, testosterone replacement at puberty is an option.
Removal of uterus dissection of Müllerian tissue away from the vas deferens/epididymis.
Laparoscopic hysterectomy may prevent the occurrences of neoplastic tissue formation.
Describe 5 alpha reductase deficiency
Occurs when testosterone is made in an XY individual but not DHT
Testes form and make AMH so Mullerian ducts regress.
Wolffian ducts develop
No external male genitals.
5 alpha reductase deficiency features
Testes form, AMH acts, testosterone acts. Internal structures form. External male structures do not fully develop.
May appear mainly female or may have ambiguous genitalia such as labioscrotal folds or clitoridean penis. The degree of the enzyme block varies and so therefore does the presentation.
Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.
Both testosterone and dihydrotestosterone (DHT) are capable of masculinising the brain in non-human primates so some brain masculinisation in utero possible with this condition.
Turner Syndrome
XO have failure of ovarian function. ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need two X’s for ovarian development.
Uterus and tubes are present, may be small or other defects in growth and development. Wide spectrum of phenotypic disorders and severity.
May be fertile, many have mosaicism. Female gender.
Hormone support of bones and uterus.
Congenital Adrenal hyperplasia
When an XX female is exposed to high levels of androgens in utero
No SRY so no testes and no AMH.
Mullerian ducts remain.
Masculinised external genitalia, but androgen levels not usually high enough to rescue Wolffian ducts.
Steroidogenesis
Check diagram on lecture slides for cholesterol conversions
Briefly describe HPA axis
CRH stimulates pituitary to secrete ACTH
ACTH stimulates rapid uptake of cholesterol into the adrenal cortex.
Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion.
Features of CAH
Completeness of the enzyme block varies. May have developed Wolffian structures and ambiguous masculinised external genitalia or hirsutism .
Early studies suggested that XX patients assigned as girls developed female gender identity, but with more masculine childhood behaviour and lower maternal interest as adults.
Also in CAH need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.
Treatment with glucocorticoids to correct feedback.
