DSD Flashcards
for how long are gonads biopotential?
until 6-7 weeks gestation
what do the cells in the testes produce?
Sertoli cells
- Mullerian-inhibiting substance (MIS aka antimullerian hormone (MUH)) ⇾ regression of mullerian ducts
Leydig cells
Testosterone and insulin-like peptide 3 (INSL3)
Testosterone ⇾ growth and differentiation of the wolffian ducts, growth of the penis and prostate
INSL3 ⇾ testicular descent
DHT ⇾ growth of prostate and fusion of labioscrotal folds
when do testes descend into the scrotum?
Inguinoscrotal phase (weeks 27 and 35) - androgens
Testosterone and INSL3 mediated
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
Endoderm develops into?
Cloaca
develops into
->Anorectal sinus and Urogenital sinus
urogenital sinus develops into:
bladder
urethra
protrate (males)
Mesoderm develops into?
Urogenital ridge which gives rise to:
- ductal system (Wolffian ducts, Mullerian ducts)
- Gonads
Adrenal cortex
Kidneys
Ureters
Ectoderm develops into what
Genital tubercle
Urethral folds
Labioscrotal folds
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 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
what is and what are types of malformative DSD
Defects in the Morphogenesis of the Urogenital Primordia
A. Defective morphogenesis of the Müllerian or Wofflian ducts
- Malformations of the vagina and uterus
- Congenital bilateral absence of the vas deferens (Cystic fibrosis)
B. Defective morphogenesis of the urogenital sinus and the primordia of the external genital
what is Dysgenetic DSD and what are types
= Abnormal Gonadal Differentiation
A. Dysgenetic DSD in 46,XY patients
- if complete, called “pure gonadal dysgenesis” or “agenesis”
B. Dysgenetic DSD in patients with mosaicisms carrying a Y chromosome
1) Ovotesticular DSD
= existence of both testicular tissue and ovarian tissue
2) Asymmetric gonadal differentiation, also known as mixed gonadal dysgenesis
= presence of a more or less dysgenetic testis on one side and a streak on the other
C. Dysgenetic DSD in 46,XX patients
1) Ovotesticular DSD
2) Testicular DSD
- SRY positive or SRY negative
D. Gonadal dysgenesis in sex chromosome aneuploidies
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
What is present in ovotesticular DSD?
existence of both testicular tissue, including seminiferous tubules, and ovarian tissue, where the presence of follicular structures containing oocytes is mandatory
may present with bilateral ovotestes—gonads carrying both testicular and ovarian tissue—one testis and one ovary or one ovotestis and one testis or ovary.
**Testicular tissue usually dysgenetic, ovarian tissue normal
Mixed gonadal dysgenesis
- what is it
- most frequent karyotype
- lab to look for it
presence of a more or less dysgenetic testis on one side and a streak on the other.
The most frequent karyotype is 45,X/46,XY, where the predominance of the 45,X on one side explains the development of the streak and the predominance of the 46,XY lineage underlies the development of the testis on the other.
labs: low AMH
what are examples of Gonadal dysgenesis in sex chromosome aneuploidies
Klinefelter
47,XYY, 47 XXX
Turner
Turner syndrome variants
What are types of Non-dysgenetic DSD with Testicular Differentiation
1) Disorders of androgen synthesis
2) Disorders of androgen action: The Androgen Insensitivity Syndrome (AIS)
3) Disorders of AMH synthesis or action
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
Example of Disorders of AMH synthesis or action
persistent Müllerian duct syndrome (PMDS)
what are types of 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
def of micro penis?
what does it mean?
Definition:
Stretched penile length < 2.5 cm in full term infant
< 2.0 cm @ 34 weeks;
< 1.5 cm @ 30 weeks
Isolated Micropenis may indicate LH/FSH deficiency -> pituitary deficiency or isolated hypogonadotropic hypogonadism
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
genes related to CAH
CYP21A2
CYP11B1
HSD3B2
Swyer syndrome
karyotype
gene
inheritance
presentation
46XY
SRY - mutated or deleted
xlinked
female genitalia
presence of mullein structure
primary hypogonadism (dysgenetic gonad)
Congenital Adrenal Hypoplasia
gene
presentation
STAR
SCC – aka CYP11A1
NROB1
Female genitalia; Adrenal Insufficiency, salt wasting
Primary hypogonadism
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)
Follistatin:
where are they made
what do they do
Made in Ovary.
Reduces pituitary FSH secretion. Involved in Ovary follicle maturation.
17a -hydroxylase/17,20-lyase deficiency
46XX: primary amenorrhea, minimal pubertal development (minimal breasts and no pubic or axillary hair development), hypertension, mild hypokalemia, and a low plasma renin activity.
○ Normal external and internal female genitalia
○ both in the adrenal glands and in the gonads, production of androgens (ie, testosterone and androstenedione) is low (hence no pubic/axillary hair) and production of ovarian estrogen is low (minimal breast development)
46XY: female or slightly atypical genitalia due to undervirilization, cryptorchidism, elevated blood pressure, low renin, and hypokalemia
DOC is high (because more Aldo produced)
– causing hypoK, low renin, HTN
issue with lice treatment
tea tree oil
estrogen
what effect does weed have on hormones
- Activation of CB1 receptor leads to stimulation of CRH and POMC
-CB1 decreases GH production
-Can also have a bimodal/temporal effect on PRL - initially elevated due to CB1 receptor but after long exposure, may decline due to increased dopamine production
-decrease activity of GnRH pulse generator and = rapid decrease in gonadotropin and sex steroid levels
-elevated PRL and decreased LH can cause the secondary amenorrhea
SO:
decreased GH
PRL initially elevated, then decreased
decreased GnRH ie LH/FSH
long term complications of CAH
Impaired fertility
Virilization
Adrenal crisis/death
Short stature (for example if not caught early/bone age closed and/or if precocious puberty)
If surgical management, impaired sexual function
Metabolic syndrome (CAH guidelines)
Osteoporosis (CAH guidelines) - if higher than average glucocorticoids
TARTs
what is DAX1
a pro-ovarian, testicular inhibitory factor that when duplicated causes feminization of males (sex reversal) and when there is loss of function causes congenital adrenal hypoplasia and sometimes ambiguous genitalia in males with unilateral or bilateral cryptorchidism. It also causes hypogonadotropic hypogonadism in males and females
what is SRY
A DNA binding protein that triggers gene interactions that lead to testicular development. Located on Y chromosome near the pseudoautosomal region
example of malformtive DSD
CF
examples of 46XY dysgenetic DSD
· Swyer syndrome (SRY inactivation/deletion) – complete cgonadal dysgenesis
· SOX9 haploinsufficiency
· SF1 mutations
· Denys-Drash, Frasier syndrome, WAGR syndrome
· ATRX mutations or deletions
· 46XY with partial duplication of Xp21.3-p21.2 – complete or partial gonadal dysgenesis → female or ambiguous genitalia
· Ovotesticular DSD
· Mixed gonadal dysgenesis
examples of nondysgenetic DSD with testicular differentiation
1) Leydig Cell Aplasia or Hypoplasia
2) Smith-Lemli-Opitz Syndrome
3) Lipoid Congenital Adrenal Hyperplasia (StAR)
4) CAH
- 17a-hydroxylase/17,20a-lyase deficiency
- P450 Oxidoreductase (POR) Deficiency
—3 affected enzymes:
—–P450c17 (preferentially its 17,20-lyase activity)
—–21-hydroxylase
—–Aromatase
- 3ß–HSD deficiency
5) 17ß–HSD deficiency
6) 5a-reductase type 2 deficiency
7) CAIS/PAIS
8) Persistent Mullerian duct syndrome
17-alpha hydroxylase deficiency CAH
labs
increased pregnenolone: 17-hydroxypregnenolone ratio
5 alpha reductase deficiency
increased T to DHT ratio
3 beta HSD deficiency
pregnenolone, 17-OH pregnenolone, DHEA/DHEAS** elevated
what to document on exam of ambiguous genitalia
- Length of genital tubercle
- Anogenital distance
- Fusion of labioscrotal folds
- Urethral opening location
- Any chordee present on the genital tubercle
- Darkening or ruggation of the labioscrotal folds
- Palpable gonads and location
- Width of the genital tubercle
what ratio of T:DHT is positive for 5 alpha reductase
T:DHT >18-20
what do Sertoli cells secrete
inhibin B and AMH
when diagnosing CAIS, what is recommended about surgery?
current recommendation is gonadectomy at completion of puberty
● Risk of malignant germ-cell tumor is low in childhood
● Deferring gonadectomy until late adolescence allows for spontaneous breast development, as well as bone mass accrual during puberty through peripheral aromatization of testosterone to estrogens.
● Tumor incidence increases in adulthood, but still low risk of progression to invasive disease.
○ Adequate tools do not currently exist that can detect a noninvasive tumor.
■ US, MRI – not sensitive enough to detect
best next step to evaluate for the presence of functioning testicular tissue?
Measure mullerian inhibitory substance and inhibin B levels
