Sexual Differentiation

Question 1

determinants of biologic sex

Answer 1

1. chromosomes
2. gonads
3. hormones
4. internal genitalia
5. external genitalia

Question 2

bipotential gonads

Answer 2

*in utero, we have bipotential gonads (could become ovaries or testicles)
*chromosomes help them “make that decision”
*default pathway = ovaries

Question 3

sex determination - female

Answer 3

1. chromosomes: XX
2. gonads: bipotential gonads remain on “default pathway” → ovaries in the absence of “other factors” (e.g. absence of SRY gene from Y chromosome)
3. hormones: granulosa cells of ovaries → estradiol
4. internal genitalia: default biology → preservation of Mullerian structures → development of uterus, fallopian tubes, upper vagina
5. external genitalia: default = female

Question 4

sex determination - male

Answer 4

1. chromosomes: XY
2. gonads: bipotential gonads deviate from the default pathway, initiated by SRY region of Y chromosome → TDF → testicles
3. hormones: Leydig cells of testes → testosterone
4. internal genitalia: anti-mullerian hormone & testosterone → involution of Mullerian structure & preservation of Wolffian structure → development of male internal genitalia
5. external genitalia: requires DHT to drive process to development of male external genitalia

Question 5

effects of Y chromosome on gonadal differentiation into testes

Answer 5

*default pathway of gonads is to become ovaries
*the presence of a specific region on the Y chromosome induces deviation from the default pathway and therefore development of testes
*SRY gene (sex-determining region of the Y chromosome) → production of TDF (testis-determining factor) → formation of testicles

Question 6

what enzyme converts testosterone to estradiol

Answer 6

*AROMATASE is the enzyme that converts testosterone into estradiol

Question 7

what does the Wolffian duct become

Answer 7

*seminal vesicles
*epididymis
*ejaculatory duct
*vas deferens

Question 8

what does the Mullerian duct become

Answer 8

*uterus
*fallopian tubes
*upper vagina

Question 9

default internal genitalia pathway

Answer 9

*default biology = biologically female
*INVOLUTION of Wolffian structures
*PRESERVATION of Mullerian structures → development of uterus, fallopian tubes, & upper vagina
*note - nothing “causes” this to happen

Question 10

development of male internal genitalia

Answer 10

*requires factors in order to deviate from default (female) pathway to the male pathway
*INVOLUTION of Mullerian structures; factor responsible = anti-mullerian hormone
*PRESERVATION of Wolffian structures; factor = testosterone → development of seminal vesicles, epididymis, ejaculatory duct, vas deferens

Question 11

what factor is responsible for inducing involution of Mullerian structures in biological males

Answer 11

*Anti-Mullerian Hormone
*produced by Sertoli cells in the testes

Question 12

what factor is responsible for inducing preservation of Wolffian structures in biological males

Answer 12

*testosterone
*produced by Leydig cells in the testes

Question 13

what hormone is responsible for inducing development of male external genitalia

Answer 13

*DHT (dihydrotestosterone)

Question 14

3 rules of sexual differentiation

Answer 14

1. natural, unperturbed state is typically FEMALE (ovary-Mullerian-external female)
2. the Y chromosome (SRY gene) produces the testes, which produces testosterone (assuming that SRY gene is intact)
3. testosterone & dihydrotestosterone produce “male anatomy” (assuming that the androgen receptors work)

Question 15

Klinefelter Syndrome - overview

Answer 15

*47, XXY
*hyalinization of seminiferous tubules & aggregation of Leydig cells
*typically manifests in adolescence
*remains a phenotypic male

Question 16

Klinefelter Syndrome - clinical features

Answer 16

*small, atrophied testes (“hyalinized”)
*low testosterone & azoospermia/infertility
*gynecomastia
*increased risk of breast cancer
*decreased facial & axillary hair
*decreased libido
*tall stature, increased leg length

Question 17

pathogenesis of gynecomastia in Klinefelter Syndrome

Answer 17

*poor production of testosterone → pituitary revs up production of FSH & LH to attempt to compensate → LH stimulates aromatase which converts testosterone to estrogen
*increased estrogen → gynecomastia and increased risk of breast cancer

Question 18

Turner Syndrome - overview

Answer 18

*45X
*short stature & pubertal delay = Turner Syndrome until proven otherwise
*ovaries do not fully develop (“streak gonads”), but default female process otherwise proceeds
*dx = karyotype

Question 19

Turner Syndrome - clinical features

Answer 19

*infancy: lymphedema, webbed neck, shield-shaped chest, cardiac defects (bicuspid aorta & coarctation), horseshoe kidney
*childhood: short stature, cubitus valgus, sensorineural hearing loss, ptosis, amblyopia
*adulthood: pubertal failure & primary amenorrhea, autoimmune thyroid disease, osteoporosis, hearing loss

note - do not have to have many/all of these features; short stature & pubertal delay = Turner Syndrome until proven otherwise

Question 20

46, XY complete gonadal dysgenesis

Answer 20

*Y chromosome has mutation or deletion of SRY gene, resulting in default female sexual development
*female phenotype with streak gonads
*risk of gonadal neoplasms
*treatment: estrogen replacement, gonadal removal due to risk of gonadoblastoma in dysgenic gonads

Question 21

androgen insensitivity syndrome

Answer 21

*karyotype XY
*testosterone and LH are high
*no androgen effect noted (due to ineffective testosterone receptors so no effects from testosterone)
*male gonadal sex (testicles & hormones) but female EXTERNAL genitalia
*therapy: estrogen replacement

Question 22

genetic female [XX] with male phenotypic features due to congenital adrenal hyperplasia

Answer 22

*enzyme deficiency, commonly in 21-hydroxylase, leading to inability to produce cortisol
*leads to buildup of precursor 17-alpha hydroxyprogesterone
*excess testosterone production by the adrenal glands
*can have normal sexual function, including fertility (only the external genitalia are affected; internal genitalia differentiate at 10 weeks gestation, but adrenal gland does not function until 12 weeks)
*represents the only life-threatening disorder of sexual differentiation
*abnormalities may vary from slight clitoromegaly to full-fledged male appearance (with apparent cryptorchidism)

Question 23

genetic female [XX] with male phenotypic features due to maternal androgen excess

Answer 23

*excess maternal androgens, either from:
-exogenous androgens OR
-ovarian or adrenal tumors

Question 24

5-alpha reductase deficiency

Answer 24

*5-alpha reductase is the enzyme that converts testosterone to dihydrotestosterone (DHT)
*DHT is important for growth and development of the penis & prostate
*results in genetic male [XY] with:
-pre puberty: FEMALE external genitalia
-post puberty: MALE external genitalia