Embryology + Endo

Question 1

Describe the embryologic development of male’s external genitalia

Answer 1

influenced by dihydrotestosterone (a product of testosterone)

3 structures:

1) genital tubercule -> glans
2) genital fold fuses and become penile shaft
3) genital swelling fuses and becomes scrotum

extra points: fusion of genital fold results in migration of the urethral meatus to tip of glans

Question 2

What structure of male reproductive organ is directly influenced by testosterone

Answer 2

epididymis
vas deferens
seminal vesicle

They are all derived from the Wolffian ducts
In male, mullerian ducts regress

Question 3

From what gonadal cells is the anti-mullerian hormone produced? what is its function?

Answer 3

Produced from the Sertoli cells (Leydig produces testosterone)

Its function is to induce regression of Mullerian ducts (which would have otherwise developed into uterus, cervix, fallopian tubes, and upper 2/3 of vagina)

Question 4

Describe the embryologic development of female’s external genitalia

Answer 4

3 structures of undifferentiated genitalia :
genital tubercule develops into the clitoris
genital fold do not fuse and develops into labia minora
genital swelling do not fuse and develops into labia majora

Bonus: the absence of testosterone and dihydrotestosterone (leydig cells) results in regression of the Wolffian ducts and development of female external genitalia

The absence of anti-mullerian hormone leads to retention of mullerian duct structure: uterus, cervix, fallopian tube, upper 2/3 vagina

Question 5

How is testosterone converted into dihydrotestosterone?

Answer 5

via 5 alpha reductase.

the development of male external genitalia is mediated via dihydrotestosterone…this is why in 5 alpha reductase deficiency there is presence of internal male organs but feminized external genitalia.

Question 6

Is the effect of testosterone and AMH local or systemic on genital differentiation?

Answer 6

Local via paracrine effect. this is why a unilateral gonadal dysgenesis will result in ipsilateral sexual differentiation pathology.

Question 7

What hormones are responsible for development of male internal/external genitalia?

Answer 7

Internal:
testosterone + AMH

External
Testosterone needs to be transformed into dihydrotestosterone via 5 a reductase to have an appropriate local effect on external male genital development.

Question 8

What is the most common DSD?

Answer 8

virilized 46 XX
For diagnostic, needs to ensure abscence of palpable gonads. Cause: excess of androgen
95 % of cases are due to congenital adrenal hyperplasia.
5% due to exogenous androgen intake.

Physiopathology CAH: deficience in conversion enzymes during steroid biosynthesis, precluding formation of cortisol +/- mineralocorticoids. Androgen are produced successfully. There is no negative feedback

deficiency in 21-dyhydroxylase is responsible for the vast majority of CAH.

Question 9

What is a mnemonic for layers of adrenal cortex ?

Answer 9

salt - sugar - sex: the deeper you go, the sweeter it gets.

then, use GFR (as in kidney) for: Glomerulosa, fasciculata, Reticularis.

Question 10

What are the 2 types of CAH?

Answer 10

Non Salt-wasting: only lacking cortisol

Salt wasting: lacking cortisol and mineralocorticoids.

Question 11

How do you dx CAH?

Answer 11

measure 17 dyhydroxyprogesterone, a proxy for 21-dihydroxylase.

Also, should measure if hyperkalemia and dehydration (salt wasting)

Confirm with US presence of mullerian organs. on DRE, you may feel the cervix.

Question 12

What is the treatment for CAH?

Answer 12

cortisol supplementation
Most identify as female (and are fertile). Surgical approach is then a feminizing genitoplasty (clitoroplasty, monsplasty, vaginoplasty)

Question 13

What are the main disorder of sexual differentiation categories?

Answer 13

46 XX with virilizing phenotype (CAH): too much androgen

46 XY with feminizing phenotype : deficit in androgen (production or reception) Classic: complete androgen insensitivity syndrome.

Ovotesticular DSD (formely true hermaphrodite) 
patient has both gonad and testis, usually in the gonad + ovotestis configuration

Question 14

What is Complete androgen insensitivity syndrome?

Answer 14

Complete external genitalia feminization in a 46XY patient. dubbed testicular feminization. 1:40000

Patient has testicles, but may be non palpable. vagina is blind ending. no mullerian organs as AMH is secreted.

Question 15

What is a classical presentation of CAIS?

Answer 15

inguinal hernia repair (bilateral…beware in female!) and suspicion of a testicle in lieux of the ovary.

send biopsy, fresh.
If diagnostic, keep testicle in situ. consult endo for testing. meet family: no testosterone imprint, gender assignment is always female.
Testicle may stay in abdo during puberty as it secretes estradiol. Management afterwards is currently debated: remove (5% cancer) vs keep (bone health, identity)

Question 16

What is anti-mullerian deficiency?

Answer 16

patient is 46 XY, has external/internal male genitalia + internal mullerian genitalia.

Question 17

What is an ovotestis?

Answer 17

a gonad which has both testicular and ovarian tissue. usually organized in a polar configuration but can be otherwise. perform deep longitudinal biopsy.

Question 18

what is the impact of an ovotestis?

Answer 18

the internal organ will be a definite form of Mullerian or Wolfian based on the adjacent gonad due to a paracrine effect.

ex: gonad / ovotestis (most frequent) : on one side there is a fallopian tube, and on the other side, a vas

Question 19

how do you dx ovotesticular dsd?

Answer 19

need a biopsy + karyotype

suspect if ambiguous genitalia,

Question 20

What is the management?

Answer 20

complex and tailored.

as a principle, with either gender, the discordant gonad should be removed.

Question 21

What is mayer-rokitansky-kuster-hauser syndrome?

Answer 21

46 XX with functional ovaries and normal external genitalia but a short, blind ending uterus and atrophic uterus.

Question 22

What is posterior labial fusion?

Answer 22

it is a fusion of the labia majora. can be mild to severe, with a scrotum like appearance in the later. not to be confuse with labia minora adhesion, which are self limited.

Question 23

Who should be assessed for DSD?

Answer 23

All patient with ambiguous genitalia

Apparent males: severe hypospad, hypospad + cryptorchidism, bilateral impalpable testicles

Apparent females: clitoromegaly, posterior labial fusion, palpable gonad

Question 24

What are the key elements in the physical exam of ambiguous genitalia newborns?

Answer 24

Palpable gonad: it is a testis or an ovotestis (even in an apparant female). it rules out a 46 XX DSD

Phalic stretch, clitoral size
evidence of a urogenital sinus
DRE: palpation of cervix/ uterus

Bronzing of areolar tissue/ genitalia: CAH

stigmata of turner: webbed neck, short, low hairline

Question 25

What is the investigation for DSD?

Answer 25

Karyotype
17-progesterone (CAH)
lytes (salt wasting CAH)
testosterone and DHT (5-a reductase)
pelvis US
Gonadal biopsy (not required for CAH)
Endoscopy if evidence of a urogenital sinus

Question 26

How should DSD be managed?

Answer 26

in an dedicated multidisciplinary group