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RC Peds Endo 2023 > DSD > Flashcards

DSD Flashcards

1
Q

MALES:
what do Sertoli cells produce?
for how long?

A

AMH
from fetus to puberty

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2
Q

FEMALES:
what do granulosa cells produce and when?

A

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.

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3
Q

When does masculinization of external genitalia begin?

what is the first step?

A

9th week gestation

lengthening of the anogenital distance

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4
Q

What tissue does gonads come from in fetal development

A

mesoderm

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5
Q

medial portion of urogenital ridges form into ?

A

adrenal cortex
gonads

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6
Q

Where do Wolffian duct arise from in embryology?

A

Intermediate mesoderm

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7
Q

when do the gonads and external genitalia begin to differentiate?

A

gonads - 6th week for XY/SRY
8th-10th week for XX

external genitalia - 9th week

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8
Q

DHT
- important point
- conversion by what from what
- where

A

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

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9
Q

estrogen
- conversion from what by what
- where

A

converted from androgens
by aromatase

granulosa cells of ovary
placenta
muscle
liver
fair follicles
adipose tissue
brain

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10
Q

what are the adrenal androgens

A

DHEA-s
androstenedione
testo

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11
Q

enzyme to make testo in testis?

A

17B-HSD-3
only in testis

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12
Q

what kind of receptor is the androgen receptor?

A

nuclear receptor

binds to ARE (androgen response elements) to the promoter regions of target genes

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13
Q

if no androgen, when do Wolffian duct regress?

A

10-12 week

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14
Q

when is maximal fetal penile growth?

A

3rd trimester

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15
Q

how do labioscrotal folds fuse in males?

A

dorsal to ventral fashion

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16
Q

SRY

A
  • SRY = sex-determining region on Y = testis-determining region

induces Sertoli cell differentiation and initiates the process of male sexual differentiation

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17
Q

SOX9
- what is it
- function

A

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

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18
Q

What triggers Sertoli cell differentiation

A

SOX9 and SF1

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19
Q

SOX9
- duplication
- deletion

A
  • duplication = 46XX sex reversal
  • deletion = 46XY sex reversal
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20
Q

DAX1
- gene
- function

A

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)

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21
Q

what triggers AMH secretion

what antagonzies

A

SOX9 is main one

SF1, GATA4, and WT1 synergize to increase SOX9-activated AMH

antagonized by DAX1

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22
Q

Mayer–Rokitansky–Küster–Hauser syndrome

A

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
23
Q

WNT4 role

A

promoting ovarian differentiation and blocking testicular differentiation

24
Q

WT1
- what is it
- function
- presentation for mutations?

A

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

25
Q

SF1

A

activates the expression of SRY, SOX9, AMH

26
Q

Hormones needed for penile growth

what if you’re missing each one

A

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

27
Q

mixed gonadal dysgenesis
- karyotype
- gonads
- risks

A
  • Most frequent karyotype 45X, 46XY
  • Asymmetric gonadal development
    ○ 1 streak + 1 dysgentic testis

** propensity to gonadoblastoma

28
Q

Sex reversal 46XY

A

SF1 mutation
SOX9 deletion
SRY loss of function
DHH mutation
CAIS
CBX2

29
Q

Sex reversal 46XX

A

SRY
SOX9 duplication
DAX1 mutation
SOX3 overexpression
WNT4

30
Q

Gene SLO

A

DHCR7
Dont Have Chol Right

31
Q

Labs to do in DSD w/u

A

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.

32
Q

Levels of AMH correlates with what

A

functional testicular tissue

33
Q

AIS cause

A

Androgen receptor defect

34
Q

mullerian develops into what
also called what

A

uterine tubes,
uterus and
upper vagina

paramesonephric

35
Q

wolffian develops into what
also called what

A

vas deferens,
epididymis and
seminal vesicles

mesonephric

36
Q

What do these develop into:

Genital tubercle
Urethral folds
Labioscrotal folds

A

Genital tubercle
Clitoris/Penis

Urethral folds
Labia minora/penile urethra

Labioscrotal folds
Labia majora/scrotum

37
Q

how are the Leydig cells stimulated

A

by hCG from placenta in the first 2 trimesters

by LH in the third trimester

38
Q

gubernaculum

A

male:
guides descent of testes into scrotum

female:
guides ovaries/ductal system into pelvis
ovarian ligament
broad ligament

39
Q

what do Sertoli cells produce and for how long

A

Sertoli cells continue to produce high amounts of AMH until puberty.

40
Q

when does masculinization of the external genitalia happen?
how does it begin?

A

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

41
Q

In 46XY dysgenic DSD complete dysgenesis, what is the phenotype?
Genes involved?

A

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

42
Q

most common karyotype for MGD
labs to look for

A

46,XX/46,XY
labs: low AMH

43
Q

what are examples of Gonadal dysgenesis in sex chromosome aneuploidies

A

Klinefelter
47,XYY, 47 XXX
Turner
Turner syndrome variants

44
Q

What are examples of Disorders of androgen synthesis

A
  • 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
45
Q

Non-dysgenetic DSD with Ovarian Differentiation

A

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

46
Q

when is cryptorchidism suggestive of DSD?

A

If bilateral and/or present with hypospadias at birth, DSD w/u suggested

47
Q

genes related to ovotesticular DSD

A

SRY (80%)
SOX9
SF1
WNT4

48
Q

Activins:
where are they made
what do they do

A

made in gonads,pituitary,placenta.
Stimulates FSH secretion

49
Q

Inhibins:
where are they made
what do they do

A

made in gonads, pituitary, placenta.

Inhibits FSH secretion, ? Role in spermatogenesis?
inhibin B is marker of functional testicular tissue (Sertoli)

50
Q

issue w lice tx

A

tea tree oil
estrogen

51
Q

effect of weed on hormones

A

decreased GH
PRL initially elevated, then decreased
decreased GnRH ie LH/FSH

52
Q

what do Sertoli cells secrete

A

inhibin B and AMH

53
Q

how to dx CAIS

A

androgen receptor sequencing
(not just genetic panel)

54
Q

adv/disadv of gonadectomy in CAIS

A

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

RC Peds Endo 2023 (17 decks)

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