DSD Flashcards
Briefly describe the process of of sex determination in the first 7 weeks
Mammalian primary sex determination has no default state. The formation of ovaries or testes is and active, gene directed process controlled by: SRY and SOX9 (male) and RSPO1/WNT/B-catenin (females).
1) at 4wks the urogentical ridge and gonads have developed from the intermediate mesoderm.
2) at 6-7wks there is a bi-potential gonad and 2 sets of ducts. the germ cells migrate into the gonad.
3) at 7wks the bi=potential gonads begin to develop into ovaries or testes.
what genes are expressed in bi-potential gonads.
WT1, SF1/NR5A1, LHX9, LIM1, PAX2, GATA4, EMX2, WNT4
which genes are responsible for the conversion of the genital ridge into the bi-potential gonad
LHX9, SF1, WT1
Whats the gene pathway of female development
Pathway is initiated by WNT4 and NR0BI (DAX1).
In the absence of SRY: RSP01 is up regulated. This then up regulates WNT4 which actiavtes the B-catenin pathway that inhibits the SOX9/male development pathway.
WNT4 also activates NR0B1 and FOXL2 which activates the ovary specific pathway.
Briefly describe the female development pathway
The mesenchyme of the ovary differentiates into thecal cells, and the surface epithilium produce cortical sex cords that surround the germ cells and become the granulosa cells.
The thecal and granulosa cells (will become follicles) secrete estrogen which induces the differentiation of the mullerian ducts into female genitalia (uterus, cervix, oviduct, upper vagina).
The absence of testosterone causes the wolffian ducts to degenerate.
Whats the gene pathway of male development
Pathway is initiated by SRY and SOX9.
SRY inhibits NR0B1 & WNT4 which inhibits the female pathway.
SRY activates SOX9, that actiavtes FGFR9 & PGD2 (which in turn activate SOX9 in a +ve feedback loop).
FGFR9 & PGD2 initiate the testis specific pathway and sertoli cell formation. They also inhibit RSP0I
SRY & SF1 are transcription factors. The are required together in the sertoli cells to tincrease the levels of transcribed amh.
Briefly describe the male development pathway
The sex cords continue to proliferate through week 8 and become the testis cords which will develop into the seminiferous tubules at puberty. The cells of the seminiferous tubule are the sertoli cells. These cells secrete AMH.
The wolffian ducts differentiate into the epididymis and the Vas Deferens.
the interstitial mesenchyme cells of the testes differentiate into the leydig cells and secret testosterone.
Name the 2 major hormones produced by the testes and their roles
AMH: Anti-Mullerian Hormone (causes mullerian ducts to regress).
Testosterone (differentiation of the wolffian ducts into the internal male genitalia).
What is testosterone converted to and whats its role
In the urogential region.
Testosterone is converted to DHT (dihydrotestosterone) by 5a-reductase-2.
Causes the morphogenesis of the penis and the prostate gland and the secondary sexual characteristics.
In very simple terms explain secondary sexual determination
Its the development of the phenotypic sex by response to hormones secreted by the ovaries.
In the presence of no/little secreted hormones the fetus will show a female phenotype due to the estrogen from the mother & placenta.
The male phenotype requires DHT.
Whats the phenotype of a male with 5a reductase 2 deficiency
Male internal genitalia (wolffian ducts differentiation controlled by testosterone).
External phenotype: blind vagina, enlarged clitoris, appear female.
At puberty the increase in testosterone causes and enlarged penis, scrotum descends and person looks male.
What is the role of estrogen
required for the complete development of both wolffian and mullerian structures.
In female: needed for mullerian differentiation.
In males: needed for fertility (regulates the absorption of water by the Vas Efferens).
For neonates with ambiguous genitalia what should be considered by the MDT
Genetics. Appearance. Surgery options. Hormonal Therapies available. Prospects of gonadal cancer. Future fertility
parents should be fully informed and involved in the decision making process.
What is the 1st line testing for neonates with ambiguous genitalia
Genetics. Pelvic ultrasound/MRI. Levels of: 17-hydroxyprogesterone. testosterone. serum electrolytes. gonadotrophins. AMH. urinary steriods.
some babies with DSD have adrenal insufficiencies that cause critical conditions: hyopglycaemia, electrolyte disorders.
screening for what deficiency is screened for in the newborn screening programm that associated with XX DSD
21-hydroxylase deficiency (most common cause of CAH).
what are some common referrals for adolescent DSDs
Inguinal hernia/tumour.
Delayed/incomplete puberty.
Primary amenorrhea/ virilisation of girls.
Breast developemtn in boys.
What is the testing for adolescents ?DSD
Genetics.
Pelvic ultrasound/MRI.
Levels of: 17-hydroxyprogesterone. testosterone. estrogen. serum electrolytes. gonadotrophins. urinary steriods. DHT (in boys). sex hormone binding globulin.
what did the 5th world congress on family law and childrens rights (2001) say were the 6 principles of ethical management of DSD
1) minimise physical risk to child. 2) minimise psychosocial risk to child. 3) preserving the potential for family. 4) preserving/promoting the capacity to have satisfying sexual relationships. 5) leaving fertility options open for the future. 6) respecting the parents wishes and beliefs.
What are DSD disorders of Sexual Development
Congenital disorders where the chromosomal/ gonadal/ anatomical sex is atypical.
newborns: ambiguous genitalia. Adolescents: atypical secondary sexual development.
Genetic diagnosis accounts for about 20% cases.
List the 3 general classes of DSD
1) sex chromosome DSD.
2) 46, XY DSD (disorders of testicular development or androgen synthesis).
3) 46, XX DSD (disorders of ovarian development or fetal androgen excess)
list two 2 DSD types of complete sex reversal
46, XX testicular DSD.
46 XY complete Gonadal Dysgenesis (CGD)
list the 2 types of mild DSD phenotype
46 XY DSD (XY feminisation)
46 XX DSD (XX virilisation)
