Sexual differentiation Flashcards
Disorder of sexual development
congenital condition in which development of chromosomal, gonadal, or phenotypic sex is atypical
Embryo sexual potential
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
Requirements for the development of repro system
germ cells
gonadal ridge
external genitalia
Indifferent gonad
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
Testis formation
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)
Mullerian duct inhibiting substance
acts locally to suppress Mullerian ducts
Mullerian duct derivatives
= paramesonephric duct internal structures: uterus tubes upper vagina
Sertoli cell function during development
Sertoli cells: produce Mullerian duct inhibiting substance (MIS or AMH)
Derived from surface epithelium, active from 6 weeks
Leydig cell function during development
Leydig cells: begin to produce testosterone at 7 weeks (likely in response to placental hCG)
- derived from mesenchyme
- active influence on Wolffian duct structures
Wolffian duct structures
epididymis, vas deferens, seminal vesicles, Ejaculatory duct
Remnants of mullerian ducts in males
utriculus prostaticulus (near seminal vesicle/prostate) Appendix testis
Ovarian determination
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
Turner syndrome repro system
have ovaries unless Y present
however, need both X’s for maintenance
Paramesonephric/Mullerian duct abnormalities
anatomical defects
e.g. primary amenorrhea with fully developed 2ndary sexual characteristics (functional ovaries)
Development of external genitalia
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
Genital tubercle derivatives
Glans penis/clitoris
Corpus cavernosum + spongiosum/vestibular bulbs
Urogenital sinus derivatives
Bulbourethralglands (Cowper)/Greater vestibular glands
Prostate gland/Urethral and parauretrhal glands
Ventral shaft of penis (penile urethral)/Labia minora
Labioscrotal swelling derivatives
Scrotum/labia majora
Mixed gonadal dysgenesis
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
Pure gonadal dysgenesis
variety of conditions
One subtype: XY with deletion of SRY (15-20%); perhaps SF1 mutations
- unambiguous female presentation
- uterus present
Androgen insensitivity syndrome
X-linked
variability of expression depending on mutation
Complete AIS
normal testes
abnormal Wolffian and Mullerian strctures
external phenotype umambiguous female
Incomplete AIS
less common
gential ambiguity/hypospadia
Dx of Androgen insensitivity syndrome
receptor studies
mutation analysis
Androgen receptor
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)
Congenital adrenal hyperplasia
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
Salt-losing CAH
no mineralocorticoids
can die of adrenal crisis
may present with hypovolemia, shock
Simple virilizing CAH
excess androgens due to shunting
some females severely virilized enough to appear umambiguously male
Late onset CAH
most common
mixes with population of PCOS females
Evaluation of infants with ambiguous genitalia
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
Dx CAH
very high serum concentration of 17-hydroxyprogesterone
dx 21-hydroxylase deficiency, classic
Females of salt-losing/simple virilizing CAH
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
males of salt-losing/simple virilizing CAH
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
Neonatal screening for CAH
17-OHP on spot card
most affected neonates have concentrations > 3500 ng/dl (105 nmol/L)
Adrenal ultrasound for CAH
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
Prenatal diagnosis of CAH
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
Tx CAH
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
Prenatal CAH therapy
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
Prenatal CAH therapy adverse effects
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
Investigations for ambiguous genitalia
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
CAH surgery
girls with classical CAH typically undergo reconstructive surgery, usually clitoroplasty/vaginoplasty
Clitoral reduction should preserve neurovascular bundle, glans, and preputial skin related to glans
Outcomes of CAH therapy (long term)
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
