DSD Flashcards
MALES:
what do Sertoli cells produce?
for how long?
AMH
from fetus to puberty
FEMALES:
what do granulosa cells produce and when?
AMH is produced at lower levels by granulosa cells of growing follicles from the twenty-third fetal week, a stage where Müllerian ducts are no longer responsive to it.
When does masculinization of external genitalia begin?
what is the first step?
9th week gestation
lengthening of the anogenital distance
What tissue does gonads come from in fetal development
mesoderm
medial portion of urogenital ridges form into ?
adrenal cortex
gonads
Where do Wolffian duct arise from in embryology?
Intermediate mesoderm
when do the gonads and external genitalia begin to differentiate?
gonads - 6th week for XY/SRY
8th-10th week for XX
external genitalia - 9th week
DHT
- important point
- conversion by what from what
- where
cannot be aromatized to estrogen
5a-reductase converts from testo
5a-reductase type 1: target tissue (urogenital sinus and fetal genital skin)
5a-reductase type 2: adrenal cortex and liver after birth
- in skin from puberty
estrogen
- conversion from what by what
- where
converted from androgens
by aromatase
granulosa cells of ovary
placenta
muscle
liver
fair follicles
adipose tissue
brain
what are the adrenal androgens
DHEA-s
androstenedione
testo
enzyme to make testo in testis?
17B-HSD-3
only in testis
what kind of receptor is the androgen receptor?
nuclear receptor
binds to ARE (androgen response elements) to the promoter regions of target genes
if no androgen, when do Wolffian duct regress?
10-12 week
when is maximal fetal penile growth?
3rd trimester
how do labioscrotal folds fuse in males?
dorsal to ventral fashion
SRY
- SRY = sex-determining region on Y = testis-determining region
induces Sertoli cell differentiation and initiates the process of male sexual differentiation
SOX9
- what is it
- function
SRY-box gene
= earliest upregulated gene in the testis pathway downstream of SRY
= master regulator of testis differentiation
Mimics SRY independently of SRY expression
1) Triggers Sertoli cell differentiation with SF1
2) Triggers AMH transcription
What triggers Sertoli cell differentiation
SOX9 and SF1
SOX9
- duplication
- deletion
- duplication = 46XX sex reversal
- deletion = 46XY sex reversal
DAX1
- gene
- function
NR0B1
1) Essential for the development of the adreno-gonadal primordia
2) Testis repressor
- Antagonizes AMH transcription
- Transcriptional repressor of many genes (including SF1 and some steroidogenic enzyme genes)
what triggers AMH secretion
what antagonzies
SOX9 is main one
SF1, GATA4, and WT1 synergize to increase SOX9-activated AMH
antagonized by DAX1
Mayer–Rokitansky–Küster–Hauser syndrome
WNT4 hetero mutation
- Masculinized ovaries and lack Müllerian ducts (or hypoplastic uterus)
- Also have Wolffian ducts → T biosynthesis
- Renal abnormalities, hearing problems, and skeletal abnormalities
WNT4 role
promoting ovarian differentiation and blocking testicular differentiation
WT1
- what is it
- function
- presentation for mutations?
Wilms tumour
- Regulates SRY
- Mutations cause gonadal dysgenesis associated with progressive renal disease
3 clinical presentations:
1) Denys-Drash – clinical triad of gonadal dysgenesis, nephropathy, and Wilms tumor
2) Frasier syndrome – gonadal dysgenesis, progressive nephropathy and gonadoblastoma.
3) WAGR syndrome – the association of Wilms tumor, aniridia, genitourinary abnormalities (ambiguous genitalia and/or gonadoblastoma), and mental retardation
SF1
activates the expression of SRY, SOX9, AMH
Hormones needed for penile growth
what if you’re missing each one
Need both testo and GH for optimal penile length
If testo without GH - penis will be a little smaller
If GH without testo - penis will be a lot smaller
mixed gonadal dysgenesis
- karyotype
- gonads
- risks
- Most frequent karyotype 45X, 46XY
- Asymmetric gonadal development
○ 1 streak + 1 dysgentic testis
** propensity to gonadoblastoma
Sex reversal 46XY
SF1 mutation
SOX9 deletion
SRY loss of function
DHH mutation
CAIS
CBX2
Sex reversal 46XX
SRY
SOX9 duplication
DAX1 mutation
SOX3 overexpression
WNT4
Gene SLO
DHCR7
Dont Have Chol Right
Labs to do in DSD w/u
1) Lytes
2) QF-PCR for SRY
3) Chromosomes - karyotype, microarray
4) HPG axis
– LH
– Testosterone (by LC/MS)
– DHT
5) Adrenal function/ Steroidogenesis
– Electrolytes
– Renin
– 17-OHP
– Testosterone
– Androstenedione
– DHEA
– 17-Preg
6) ACTH stim in all patients with DSD:
7) HCG stim only if male and looking at androgens produced in the testes
8) Evaluate testis presence/function
– AMH (Sertoli)
– Inhibin B (Sertoli)
– Testosterone synthesis stimulation with hCG
9) Urinalysis: proteinuria
(Denys-Drash syndrome)
10) Cholesterol metabolites (plasma sterols): cholesterol metabolism defects (SLO)
11) Molecular testing: If there is evidence supporting a monogenic etiology, molecular investigations either through targeted or multigene panel testing should be undertaken.
Levels of AMH correlates with what
functional testicular tissue
AIS cause
Androgen receptor defect
mullerian develops into what
also called what
uterine tubes,
uterus and
upper vagina
paramesonephric
wolffian develops into what
also called what
vas deferens,
epididymis and
seminal vesicles
mesonephric
What do these develop into:
Genital tubercle
Urethral folds
Labioscrotal folds
Genital tubercle
Clitoris/Penis
Urethral folds
Labia minora/penile urethra
Labioscrotal folds
Labia majora/scrotum
how are the Leydig cells stimulated
by hCG from placenta in the first 2 trimesters
by LH in the third trimester
gubernaculum
male:
guides descent of testes into scrotum
female:
guides ovaries/ductal system into pelvis
ovarian ligament
broad ligament
what do Sertoli cells produce and for how long
Sertoli cells continue to produce high amounts of AMH until puberty.
when does masculinization of the external genitalia happen?
how does it begin?
begins during the ninth fetal week in response to DHT
characterized by lengthening of the anogenital distance
Subsequently labioscrotal folds fuse in a dorsal to ventral fashion
In 46XY dysgenic DSD complete dysgenesis, what is the phenotype?
Genes involved?
the fetus is completely feminized, owing to the lack of the two testicular hormones involved in fetal sex differentiation
SRY mutations, SF1 mutations, WT1 mutations
most common karyotype for MGD
labs to look for
46,XX/46,XY
labs: low AMH
what are examples of Gonadal dysgenesis in sex chromosome aneuploidies
Klinefelter
47,XYY, 47 XXX
Turner
Turner syndrome variants
What are examples of Disorders of androgen synthesis
- Leydig Cell Aplasia or Hypoplasia - Defects in LHCG Receptor
- Smith-Lemli-Opitz Syndrome - Defect of Cholesterol Biosynthesis
- Lipoid Congenital Adrenal Hyperplasia - Defects of Pregnenolone Biosynthesis
- P450c17 Deficiency - Defects of Androstenedione and DHEA Biosynthesis
- P450 Oxidoreductase (POR) Deficiency
- 3β-HSD Deficiency - Defects of Δ4-Steroid Biosynthesis
- 17β-HSD Deficiency - Defect of Testosterone Biosynthesis
- 5α-reductase type 2 - Defects of DHT Biosynthesis
- MAMLD1 - Other Defects of Androgen Biosynthesis
Non-dysgenetic DSD with Ovarian Differentiation
A. Disorders of adrenal steroidogenesis
21-Hydroxylase Deficiency (21-OHD)
11β-Hydroxylase Deficiency
3β-Hydroxysteroid Dehydrogenase Deficiency
B. Glucocorticoid receptor gene mutation
C. Placental aromatase deficiency
D. P450 oxidoreductase deficiency
E. Maternal sources: Androgens and progestogens
when is cryptorchidism suggestive of DSD?
If bilateral and/or present with hypospadias at birth, DSD w/u suggested
genes related to ovotesticular DSD
SRY (80%)
SOX9
SF1
WNT4
Activins:
where are they made
what do they do
made in gonads,pituitary,placenta.
Stimulates FSH secretion
Inhibins:
where are they made
what do they do
made in gonads, pituitary, placenta.
Inhibits FSH secretion, ? Role in spermatogenesis?
inhibin B is marker of functional testicular tissue (Sertoli)
issue w lice tx
tea tree oil
estrogen
effect of weed on hormones
decreased GH
PRL initially elevated, then decreased
decreased GnRH ie LH/FSH
what do Sertoli cells secrete
inhibin B and AMH
how to dx CAIS
androgen receptor sequencing
(not just genetic panel)
adv/disadv of gonadectomy in CAIS
for: risk of malignant transformation in gonads, Mostly occurring post pubertally
against: can benefit from endogenous testo production and peripheral conversion to estrogen and avoid exogenous steroid replacement
