2/15 Disorders of Puberty - Radovick Flashcards
endocrine system graphic

female HPG axis
hypothal_GnRH neurons : GnRH
ant pituitary_gonadotropes : FSH & LH
ovaries : P4 (progesterone) & E2 (estradiol)
→→→ endometrium, female phenotype
feedback
- estradiol has two types of feedback
- positive feedback at level of GnRH neuron (hypothal) and pituitary → midcycle surge of LH → ovulation
- negative feedback: high levels of E2 decr levels of GnRH, FSH, LH

male HPG axis
hypothal_GnRH neurons : GnRH
ant pituitary_gonadotropes : FSH & LH
testes : T (testosterone)
→→→ male phenotype, spermatogenesis
feedback
- only one type of feedback
- negative feedback: high levels of T decr levels of GnRH, FSH, LH
GnRH
gonadotropin releasing hormone
decapeptide synth’d via cleavage from pre-pro-GnRH protein in preoptic nuclei
GnRH secretion is PULSATILE

migration of GnRH neurons
disease of non-migration
GnRH neurons and olfactory neurons move from olfactory placode through cribriform plate to anterior hypothalamus
**MIGRATION IS CRITICAL
- no migration? disease
Kallmann Syndrome: hypothalamic hypogonadism (assoc with anosmia)
- KAL1 protein directs migration (adhesion protein)
- if mutated? GnRH deficiency → anosmia, hypogonadism
GnRH receptor signaling
GnRH hits GnRH receptor in ant pit → FSH, LH synthesis and secretion via stimulation of subunit genes
ALSO stimulates subunit genes
desensitization of GnRH has effects on pulsatility of LH (more) and FSH (some)
- lack of cytoplasmic tail → reduced receptor desensitization and internalization
pituitary and placental glycoprotein family
- LH
- FSH
- TSH
- hCG
- common alpha subunit + hormone-specific beta subunit
- glycosylation essential for fx
pulsatility of GnRH
pulsatility of GnRH → pulstility of LH/FSH secretion
continuous infusion?
no pulsatility of LH/FSH
implication: if you have too much FSH/LH (ex. precocious puberty) and you need to tone it down → cont infusion GnRH is an option → hypogonadism
two cell hypothesis of ovary
-
theca cell: LH receptors
- LH receptors are Gprotein-coupled → Gs → make adenylyl cyclase → incr cAMP
- make androstenedione
-
granulosa cell: FSH receptors
- FSH receptors are also Gprotein-coupled → make adenylyl cyclase → incr cAMP → conversion of androstenedione from theca cells into E2 (estradiol)

testes
-
Leydig cell: LH receptors
- make testosterone
-
Sertoli cell: FSH receptors
- concentrates testosterone from Leydig cells → req for spermatogenesis

kisspeptin
pubertal trigger
- upstream of GnRH
- important in triggering puberty and ovulatory surge of gonadotropins

HPG axis summary

puberty
definition
puberty: hormones & processes
adrenarche: hormones & processes
period of life during which acquisition of secondary sexual characteristics occurs
puberty
hypothal:GnRH → pituitary:FSH/LH → testes/ovaries:testosterone/estradiol
GONADARCHE: incr size of testes (due to testosterone incr)
THELARCHE: onset of breast devpt
adrenarche
pituitary:ACTH → adrenal:DHEA/DHEAS → adrenal androgens
TANNER2-3: PUBIC HAIR

Tanner stage
breasts
stage1 : no breast tissue
stage2 : breast bud; elevation under areola (onset ~10y)
stage3: enlargement of breast tissue beyond areola, no separation of contours
stage4 : projection of areola and papilla to form secondary mound above level of breast
stage5 : mature stage
Tanner stage
pubic hair
stage1 : no pubic hair
stage2 : sparge growth of long, pigmented hair on labia
stage3 : darker, coarser, curlier hair on pubis
stage4 : adult-type hair, but less quantity
stage5 : adult0type and quantity, inverted triangle
Tanner stage
male genitalia
**testicular size is the best way to stage males
stage1 : preadolescent
stage2 : thinning, reddening of scrotum
stage3 : enlargement of penis length, curly pubic hair
stage4 : enlargement of penis length/breadth; development of glans, testes
stage5 : adult size and shape, pubic hair on thigh, adult testicular size
females @ time of menarche
males @ time of facial hair
female menarche
- relatively late event in pubertal devpt
- onset: 12-13yr
- breasts usually stage 4 (bc started at 10y)
- occurs significantly after max growth velocity
male facial hair
- onset: 15yr
- genital devpt nearly complete
- occurs after but still close to max growth velocity
abnormalities of puberty
1. delayed (hypogonadism)
- CENTRAL : hypogonadotropic
- PERIPHERAL (primary) : hypergonadotropic
- females*: no breast devpt by 13, no menses by 16
- males*: no testicular devpt by 14
2. precocious
- CENTRAL : gonadotrophic-dependent aka GDPP
- PERIPHERAL : gonadotropin-indep aka GIPP
- females:* breast devpt before 8
- males:* incr testicular size before 9
hypogonadism
central vs peripheral
central (85%) : inability to make GnRH, LH, FSH
- constitutional delay of growth, puberty 50
- fxal hypogonadotropic hypogonadism (20)
- nutrition, stress, exercise, hyperPRLemia
- permanent hypogonadotropic hypogonadism (15)
- genetic, tumors, vascular
peripheral (15%) : increased GnRH, LH, FSH
- gonadal dysgenesis
- Turner, Klinefelter
- gonadal failure
- autoimmune, chemotx, radiation, torsion

Klinefelter Syndrome
XXY
- hypogonadism w very small testes

Turner Syndrome
XO
small dysfx ovaries → no estrogen produced
elevated FSH/LH

tx of delayed puberty
females
- ethinyl estradiol PO or transdermal estradiol
- progestagen when menstrual bleeding starts
males
- testosterone IM or transdermal
induction of fertility in hypogonadotropic hypogonadism:
- pulsatile GnRH
- combo FSH, hCG tx
precocious puberty
central (90%) : gonadotropin-dependent → incr in GnRH, LH, GSH, sex steroids
- idiopathic (most common)
- general CNS insult
- radiation, infl, trauma
- CNS tumors
- hamartomas
peripheral (10%) : gonadotropin-indep → low LH, FSH; incr sex steroids
- gonad : sex steroid secreting tumors
- adrenal : sex steroid secreting tumors, CAH
- exog estrogen/androgen
- McCune-Albright syndrome: activating mutation in Galpha-s
- females : ovarian cysts
- males : hCG secreting tumors, familial testotoxicosis (activation mutation in LH receptor)

tx of central precocious puberty
- GnRH agonists (analogs) → induce pituitary desensitization
* can have initial flare (leuprolide + histrelin) - GnRH antagonists (rarely used)

summary
