Sexual differentiation

Question 1

Disorder of sexual development

Answer 1

congenital condition in which development of chromosomal, gonadal, or phenotypic sex is atypical

Question 2

Embryo sexual potential

Answer 2

bipotential
whether they’re XX/XY, each capable of producing either a male or female repro system
all three germ cells, gonadal ridge and external structures are the same

Question 3

Requirements for the development of repro system

Answer 3

germ cells
gonadal ridge
external genitalia

Question 4

Indifferent gonad

Answer 4

4.5-6 wks
Indistinguishable as male or female gonad
from gonadal ridge: interactive gene functions
primordial germ cells migrate from area of yolk sac
have been undergoing mitotic increases in number

Question 5

Testis formation

Answer 5

6 wks
require presence of Y chromosome (SRY region at Yp)
testis organization under active and local control of SRY gene product
Other genes crucial (SOX9, DAX1, WT1, etc)

Question 6

Mullerian duct inhibiting substance

Answer 6

acts locally to suppress Mullerian ducts

Question 7

Mullerian duct derivatives

Answer 7

= paramesonephric duct
internal structures:
uterus
tubes
upper vagina

Question 8

Sertoli cell function during development

Answer 8

Sertoli cells: produce Mullerian duct inhibiting substance (MIS or AMH)
Derived from surface epithelium, active from 6 weeks

Question 9

Leydig cell function during development

Answer 9

Leydig cells: begin to produce testosterone at 7 weeks (likely in response to placental hCG)

• derived from mesenchyme
• active influence on Wolffian duct structures

Question 10

Wolffian duct structures

Answer 10

epididymis, vas deferens, seminal vesicles, Ejaculatory duct

Question 11

Remnants of mullerian ducts in males

Answer 11

utriculus prostaticulus (near seminal vesicle/prostate)
Appendix testis

Question 12

Ovarian determination

Answer 12

10-11 wks
maybe sooner? but definitely lags behind testicular development
initially thought to be passive but there seems to be genes involved with active induction of ovary
Mesonephric duct degenerates, paramesonephric duct develops

Question 13

Turner syndrome repro system

Answer 13

have ovaries unless Y present

however, need both X’s for maintenance

Question 14

Paramesonephric/Mullerian duct abnormalities

Answer 14

anatomical defects

e.g. primary amenorrhea with fully developed 2ndary sexual characteristics (functional ovaries)

Question 15

Development of external genitalia

Answer 15

initially indifferent
Male: tubercle –> penis
- genital swellings –> fuse –> scrotum
- under influence of DHT (need 5alpha reductase to convert testosterone –> DHT)

Female: looks similar to male until 9-10 wks

Question 16

Genital tubercle derivatives

Answer 16

Glans penis/clitoris

Corpus cavernosum + spongiosum/vestibular bulbs

Question 17

Urogenital sinus derivatives

Answer 17

Bulbourethralglands (Cowper)/Greater vestibular glands
Prostate gland/Urethral and parauretrhal glands
Ventral shaft of penis (penile urethral)/Labia minora

Question 18

Labioscrotal swelling derivatives

Answer 18

Scrotum/labia majora

Question 19

Mixed gonadal dysgenesis

Answer 19

variant of Turner with mosaicism involving Y
most commonly: 45, X/46, XY
Testis determination will depend on proportions of cells containing Y
Sex chromosome DSD

Question 20

Pure gonadal dysgenesis

Answer 20

variety of conditions
One subtype: XY with deletion of SRY (15-20%); perhaps SF1 mutations
- unambiguous female presentation
- uterus present

Question 21

Androgen insensitivity syndrome

Answer 21

X-linked

variability of expression depending on mutation

Question 22

Complete AIS

Answer 22

normal testes
abnormal Wolffian and Mullerian strctures
external phenotype umambiguous female

Question 23

Incomplete AIS

Answer 23

less common

gential ambiguity/hypospadia

Question 24

Dx of Androgen insensitivity syndrome

Answer 24

receptor studies

mutation analysis

Question 25

Androgen receptor

Answer 25

encoded by X-linked androgen receptor gene (Xq13) similar to other steroid receptors necessary for androgen-sensitive cells (Wolffian duct, external genitalia, brain, areas of sex-specific body hair, etc)

Question 26

Congenital adrenal hyperplasia

Answer 26

commonest cause of genital ambiguity several types involving steroid hormone biosynthesis 21-hydroxylase deficiency - involves structural gene for adrenal cytochrome P450 specific for steroid 21-hydroxylation Buildup of 17-hydroxyprogesterone

Question 27

Salt-losing CAH

Answer 27

no mineralocorticoids can die of adrenal crisis may present with hypovolemia, shock

Question 28

Simple virilizing CAH

Answer 28

excess androgens due to shunting | some females severely virilized enough to appear umambiguously male

Question 29

Late onset CAH

Answer 29

most common | mixes with population of PCOS females

Question 30

Evaluation of infants with ambiguous genitalia

Answer 30

``` some may have life-threatening conditions that need to be assessed immediately - e.g. heart, renal Look carefully at genitalia Look for other anomalies Document adequacy of urinary tract metabolic status - glucose, electrolytes chromosomes, 17-OH progesterone review pregnancy/family history reassure parents; have team approach ```

Question 31

Dx CAH

Answer 31

very high serum concentration of 17-hydroxyprogesterone | dx 21-hydroxylase deficiency, classic

Question 32

Females of salt-losing/simple virilizing CAH

Answer 32

neonate presentation: ambiguous genitalia (clitoral enlargement, common urethral-vaginal orifice) Partial/complete fusion of labial folds and rostral migration of urogenital orifice may also occur internal female reproductive organs normal rare instances: ambiguous genitalia may not be identified - may present with adrenal crisis at 1-2 wks

Question 33

males of salt-losing/simple virilizing CAH

Answer 33

neonate: salt-losing adrenal crisis Toddler: signs of puberty (non-salt losing form) newborn males: no overt signs of CAH, although phallic enlargement/scrotal hyperpigmentation sometimes present Typically diagnosed before they develop clinical symptom

Question 34

Neonatal screening for CAH

Answer 34

17-OHP on spot card | most affected neonates have concentrations > 3500 ng/dl (105 nmol/L)

Question 35

Adrenal ultrasound for CAH

Answer 35

potential adjunctive test for CAH in neonates wiht ambiguous genitalia and/or life threatening salt loss, when diagnosis is equivocal based upon ohter testing adrenal limb width >4 mm, lobulated surface, or abnormal echogenicity

Question 36

Prenatal diagnosis of CAH

Answer 36

considered when fetus is known to be at risk due to affeted sibling/partners are carriers Measurements of amniotic fluid 17-OHP, HLA typing of fetal cells, molecular analysis of fetal CYp21A2 in AC or CVS method of choice: molecular analysis of CYP21A2 gene

Question 37

Tx CAH

Answer 37

providing GC in sufficient doses to reduce excess CRH/ACTH and hyperandrogenemia Salt-losing form: MC given to restore serum electrolyte concentrations and extracellular fluid volume to normal

Question 38

Prenatal CAH therapy

Answer 38

Maternal administration of dexamethasone - not degraded by placenta, crosses into fetal circulation - suppression of fetal pituitary ACTH - initiated as soon as pregnancy recognized - if not begun at 9 wks, don't give it at all - d/c if genetic testing reveals male /unaffected female fetus 85% of pretreated females born with N/slightly virilized genitalia

Question 39

Prenatal CAH therapy adverse effects

Answer 39

may have adverse effects, long-term risks unknown Mother: increased appetite, early and excessive wt gain, edema, striae, SSx of Cushing's Fetus: postnatal failure to thrive, psychomotor developmental delay

Question 40

Investigations for ambiguous genitalia

Answer 40

Hx/P Pelvic US and possibly adrenals karyotype/FISH for sex chromosome (SRY) 17-OHP nonpalpable gonads - presumed to have CAH, empirically treated until dx is confirmed/excluded - after 17OHP sample drawn, tx with GC + MC + NaCl in all infants to prevent adrenal crisis

Question 41

CAH surgery

Answer 41

girls with classical CAH typically undergo reconstructive surgery, usually clitoroplasty/vaginoplasty Clitoral reduction should preserve neurovascular bundle, glans, and preputial skin related to glans

Question 42

Outcomes of CAH therapy (long term)

Answer 42

Growth: fewer pts reach adult height due to hyperandrogenism/hypercortisolism Bone: dependent upon age, but tend to have lower bone mineral density May have irregular menstrual cycles Testis: ectopic adrenal tissue located in testes commonly found in males with CAH, can interfere with testicular fxn resulting in infertility Obesity: complication in GC-txed patients with 21-hydroxylase deficiency Mortality: 3x in 1-4 y, due to adrenal crisis after an infection education of parents/caregivers important