Disorders of Sex Development (Week 7--Vilain)

Question 1

How common are disorders of sex development (DSDs)?

Answer 1

1/5,000 “classic” ambiguous genitalia

1/100 all pathologies of genital tract (hypospadias, cryptorchidism, clitoris hypertrophy)

Question 2

2 steps that cause sexual development of male genitals

Answer 2

1) Sex determination: Y chromosome needed
2) Sex differentiation: need testosterone for internal genitalia, DHT for external genitalia, and MIS for regression of Mullerian ducts

Question 3

What are the 2 kinds of DSDs depending on where the problem is?

Answer 3

1) If sex determination problem, get gonadal dysgenesis (abnormal gonads, ovo-testicular DSD, “true hermaphorditism”)
2) If sex differentiation problem, get normal gonad development but abnomal development of genitalia; male pseudohermaphroditism (XY with testes but external female genitalia) or female pseudohermaphroditism (XX with ovaries who have masculinized or ambiguous genitalia)

Question 4

What is the most common example of abnormal gonads?

Answer 4

Klinefelter syndrome: 1/1,000; 47 XXY (azoospermia, tall, gynecomastia; man w/penis that looks femininebc of hips and boobs)

Turner syndrome: 1/2,500; 45 X (lymphedema, short, webbed neck, widely spaced nipples, X from father; female w/vagina that looks a little masculine)

Question 5

XX testicular DSD

Answer 5

XX male has penis

Seminiferous tubules look normal but no sperm inside

Majority of XX males have SRY translocation, 10% XX ovotesticular DSD have SRY

Genes necessary for spermatogenesis are on the long arm of Y and SRY is on the short arm so need whole chromosome for spermatogenesis (XX testicular person probably got SHORT arm if has penis but no sperm in seminiferous tubules)

Question 6

XY female with gonadal dysgenesis

Answer 6

Ovary degenerated, no eggs because has Y chromosome

Looks female but cannot go through puberty bc no ovaries!

10-15% XY females with gonadal dysgenesis have mutation of SRY

Question 7

What is SRY responsible for?

Answer 7

Forms testes

Necessary and sufficient for male determination (if everything else is normal)

Majority of XX males have SRY translocation, 10% XX ovotesticular DSD have SRY, 10-15% XY females with gonadal dysgenesis have mutation of SRY

Note: Genes necessary for spermatogenesis are on the long arm of Y and SRY is on the short arm so need whole chromosome for spermatogenesis

Question 8

Molecular mechanism of SRY

Answer 8

SRY upregulates (with Fgf9) and maintains Sox9 (after SF1 has initiated Sox9) and Sox9 is the main driver of male pathway

Question 9

What pathways are battling for sex determination?

Answer 9

Sox9 for male

Beta-catenin and Foxl2 for female

Note: this happens at the genital ridge

Question 10

Pathologies of sex differentiation

Answer 10

Feminized XY: defect of synthesis of testosterone or androgen resistance

Masculinized XX: excess of androgens (meds, tumor, CAH)

Question 11

Congenital Adrenal Hyperplasia (CAH)

Answer 11

Most common cause of intersexuality (1/5,000)

21-hydroxylase deficiency in 85% of cases

Autosomal recessive

XX that is virilized

Treatment: GC and mineralocorticoid replacement (make sure they don’t die!!); plastic surgery of external genitalia maybe

Question 12

Androgen insensitivity syndrome

Answer 12

Eva from Nip/Tuck!

AKA Testicular Feminization

Androgen receptor doesn’t work to detect T or DHT

X-linked mutation in androgen receptor

Normal testes (bc have SRY) but not descended, and female external genitalia

High testosterone, estrogen, LH

No uterus (because normal secretion of MIS inhibited that)

Can be complete, partial or mild

Question 13

5 alpha reductase deficiency

Answer 13

Can’t make DHT

Inside masculine (Wolffian ducts, epididymis, vas, seminal vesicles) but outside ambiguous (can’t make external genitalia or prostate) until puberty when get increased testosterone to cause masculinization (enough T will act like DHT to cause external genitals)

“Penis at 12”

Question 14

Persistent Mullerian Duct Syndrome

Answer 14

“Males with uterus”

MIS not secreted, so form a uterus on the inside

Normal external and internal male genitalia though

Could be because no Sertoli cells or because of lack of anti-mullerian hormone

Question 15

How can we treat CAH prenatally?

Answer 15

Pregnant mother takes high doses of dexamethasone to suppress ACTH secretion (so not as much stimulation of adrenals to produce as much testosterone) –> fetuses have much less genital ambiguity

However, only 1/8 of fetuses treated would really need this so would treat 7 unnecessarily