Disorders of Sexual Differentiation

Question 1

three broad classifications of disorders of sexual differentiation

Answer 1

1. disorders of gonadal differentiation and development
2. pseudohermaphrodotism
3. unclassified/miscellaneous forms

Question 2

47, XXY

Answer 2

• klinefelter’s syndrome
• can also be 48, XXYY, or mosaic 46 XY/47 XXY
• most common major abnormality, seminiferous tubular dysgensis

Question 3

45, X0

Answer 3

• turner’s syndrome
• oocytes degenerate leaving streak gonads at birth

Question 4

46, XX males: sex reversal

Answer 4

• probably translocation of Y material (SRY) to X chromosome, or mutation of a gene on the X chromosome
• normal testes and external genitalia, but 10% have hypospadias

Question 5

46, XY: complete gonadal dysgenesis

Answer 5

• male genotype, dysfunctional SRY
• get phenotypic female with sexual infantism
• increased risk of germ cell tumors
• manage this risk with gonadectomy and hormone replacement

Question 6

46, XY: embryonic testicular regression

Answer 6

• evidence of prior testicular function
• regression may be from a mutation, teratogen, or bilateral torsion

Question 7

klinefelter’s syndrome

Answer 7

• 47, XXY
• X-inactivation, but some genes escape inactivation. it is these genes that cause all the problems (remember a lot of these are also located on the Y chromosome, so have three copies in this case)
• look for the barr body!
• 1 in 500 people: this is the most frequent cause of hypogonadism
• some instances of cryptorchidism, including azoospermia (no sperm in ejaculate)
• micropenis
• small, firm testes
• gynecomastia (breast development)

Question 8

describe the pathway by which small, firm testes occur in klinefelter’s syndrome (slide 90)

Answer 8

• hyalinization of seminiferous tubules
• loss of sertoli cells, so less inhibin secretion
• increased FSH, which stimulates aromatase in leydig cells
• this increases estrogen (because aromatase turns all testosterone into estrogen)
• this of course decreases testosterone
• now there is no testosterone negative feedback, so increase LH, causing leydig cell hyperplasia
• this leads to leydig cell nodules

Question 9

turner’s syndrome

Answer 9

• 45, X0
• no barr body
• 1:2500 - less common because most spontaneously abort because need second X chromosome
• streak ovaries: no germ cells, just stromal cells
• no oogenesis
• risk of dysgerminoma (tumor)
• ovaries don’t make estrogen, so no negative feedback leads to increased LH and FSH
• this is the most common gonadal disorder causing primary amenorrhea
• short stature, webbed neck, wide spacing of nipples

Question 10

mixed gonadal dysgenesis

Answer 10

• short stature and streak ovaries (no germinal tissue) are asosciated with other forms of gonadal dysgenesis including XX and XY gonadal dysgenesis
• however, these are NOT associated with specific somatic abnormalities that are found in turner’s syndrome
• these somatic abnormalities include epicanthal folds, low-set ears, webbed neck, lymphedema of hands and feet, renal malformations, and aortic coarctation (narrowing)

Question 11

what is pseudohermaphrodotism?

Answer 11

• gonads are one sex, but there are one or more contraindications in morphologic criteria of sex
• in other words, they look like they have both genders, but one is a pseudomanifestation
• in female P, the person is genetically female (XX), but has male secondary sex characteristics
• in male p, person is genetically male (XY), but has female secondary sex characteristics

Question 12

common and rare causes of female pseudohermaphrodotism

Answer 12

• common: congenital adrenal hyperplasia
• rare: maternal ingestion of androgens or virilizing tumors in the mother

Question 13

possible causes of male pseudohermaphrodotism

Answer 13

• leydig cell aplasia
• disorders of testosterone/DHT biosynthesis
• androgen receptor defects
• impaired AMH/MIS from sertoli cells, or impaired action of AMH/MIS

Question 14

prader/quigley stages (slide 92)

Answer 14

• prader: virilization
• quigley: feminization

Question 15

go over and understand diagram on slide 92

Answer 15

PLZ

Question 16

3-beta-HSD deficiency in male pseudohermaphrodotism (slide 93)

Answer 16

• shuts down cortisol and aldosterone synthesis, causing adrenal hyperplasia
• also shuts down androgen synthesis, so no testosterone. this causes two things: ambiguous genitalia and cryptorchidism

Question 17

17-beta-HSD mutation in male pseudohermaphrodotism (slide 94)

Answer 17

• leads to no testosterone, so no DHT
• shunts precursors to estrogens, so elevated estrogens
• there is a lot of estrone made (aromatase makes this version, and aromatase is normal). estrone is not as potent as estradiol, so it does not have negative feedback on LH and FSH
• so, have increased LH and FSH levels
• phenotypically female
• virilization at puberty

Question 18

5-alpha-reductase mutation in male pseudohermaphrodotism

Answer 18

• female genitalia
• partial virilization at puberty
• elevated testosterone to DHT ratio
• genetic males, 46, XY
• autosomal recessive, only people who have mutations in both copies of SRD5A2 gene and are genetically male will have the characteristic signs of 5-alpha-reductase type II deficiency

Question 19

describe development of a genetic male with a 5-alpha-reductase deficiency

Answer 19

1. at 18 months, appearance is female, though undescended testes are present
2. without DHT in utero, external genitalia develop female, but gonadal tissue is that of normal male
3. remember that we need DHT in utero for external genitalia to develop as male
4. just before puberty, right before huge testosterone outpouring, phenotype is still female
5. testosterone surge happens at puberty, and this changes the phenotype to male. voice deepens, testes descent, erection and ejaculation begin, male psychosexual orientation develops. this can happen even without DHT because so much testosterone accumulates
   - they will look like men for the rest of their lives, though will have little beard growth, no hairline recession, no acne, and small prostate

Question 20

deficiency of androgen receptor in male pseudohermaphrodotism

Answer 20

• androgen insensitivity/testicular feminization syndrome
• genetic males, 46, XY
• X-linked recessive
• this is the largest single entity that leads to 46, XY undermasculinized genitalia
• point mutation of glycine 708 for glutamine
• testosterone synthesis is normal
• no androgen receptor means no differentiation of wolffian duct and urogenital sinus
• accumulated testosterone gets aromatized in to estradiol, which causes adult female secondary sex characteristics
• AMH/MIS from sertoli cells during fetal development is normal, so mullerian duct regresses and there is no uterus

Question 21

three categories of androgen insensitivity syndrome

Answer 21

• complete (CAIS): female phenotype
• partial (PAIS): partially masculinized
• mild: male phenotype
• CAIS and PAIS patients with female genitalia think like male: this makes for complex gender assignment

Question 22

deficiency of AMH/MIS receptor in male pseudohermaphrodotism

Answer 22

single base pair mutation encoding premature stop codon in MIS type II receptor leads to persistent mullerian duct syndrome in canines