Neuroendocrinology Flashcards
Hypothalamic neurohormones
and their
Anterior pituitary hormones
- GnRH > FSH/LH (gonadotrophs)
- CRH > ACTH (& MSH) (corticotrophs)
- TRH > TSH (thyrotrophs)
- Dopamine –| Prolactin (lactotrophs)
- GHRH/Somatostatin > GH (somatotrophs)
Where is GnRH produced?
Hypothalamus (medial, basal; median eminence) - arcuate nucleus
Where do GnRH cells originate from?
Olfactory neurons
Anosmia
No puberty
Kallman syndrome
Pathophysiology behind Kallman syndrome
Failure of olfactory axonal and GnRH neuronal migration from the olfactory placode
- No GnRH
- No smell
Three mutations causing Kallman syndrome
Mutations in:
- KAL-1 gene, X-linked (increased frequency 5-7x in males): deficient cell adhesion and protease inhibition essential for neuronal migration
- FGFR-1 gene, AD or AR
- Abnormal tyrosine kinase receptors
GnRH precursor hormone –>
GnRH (decapeptide) + GAP (inhibits prolactin, stimulates gonadotropins)
What is the half-life of GnRH?
2-4 minutes
Discuss pathway of GnRH hormone release
- GnRH synthesis: median eminence/arcuate nucleus of hypothalamus
- GnRH transport down axon: GnRH tuberoinfundibular tract
- Hypophyseal vein (every 1-2 hours) to the pituitary
*GnRH sent directly to the pituitary via the hypophyseal portal circulation rather than systemic circulation, in order to act quickly
Describe the different feedback loops
Long: estrogen/progesterone > hypothalamus and pituitary
Short: LH/FSH > hypothalamus
Ultra-Short: GnRH > hypothalamus (using dopamine, NE, endorphin, serotonin, melatonin)
In follicular phase:
- GnRH frequency is fast/slow
- GnRH amplitude is high/low
In luteal phase:
- GnRH frequency is fast/slow
- GnRH amplitude is high/low
When is pulse amplitude the HIGHEST?
Which gonadotropin does a slow frequency GnRH favor?
*Use LH frequency to measure this as the half-life of FSH is too long to measure accurately
Think of climbing up a mountain: start fast, end slow up at the top, with greater amplitude
Also think of LH being favored in the follicular/early luteal phase to mount LH surge (need fast GnRH pulse frequency for this)
In follicular phase:
- GnRH frequency is FAST
- GnRH amplitude is LOW
In luteal phase:
- GnRH frequency is SLOW
- GnRH amplitude is HIGH
Highest pulse amplitude in the EARLY luteal phase, immediately before ovulation
Slow pulse frequency of GnRH favors > FSH
Where is dopamine synthesized?
Arcuate and periventricular nucleus
What does dopamine do?
Dopamine suppresses prolactin
Prolactin suppresses GnRH release
(So dopamine normally functions to allow normal GnRH and gonadotropin release)
What does norepinephrine do?
Norepinephrine stimulates GnRH secretion in the presence of estrogen via neuropeptide Y (NPY)
NE in absence of estrogen inhibits GnRH secretion
What does neuropeptide Y (NPY) do?
- NPY stimulates eating behavior (in response to insulin and leptin)
- Stimulates fast pulsatile release of GnRH > favors LH production (in response to high estrogen levels)
- In contrast, prior to puberty, NPY is the “brake” preventing puberty onset (given absence of estrogen)
What does kisspeptin do?
- “First kiss” > then puberty
- Initiates GnRH secretion at puberty if enough leptin
- Regulated by estrogen/progesterone
What occurs with kisspeptin GPR54 mutations?
Hypo hypo > delayed puberty (decreased GnRH secretion)
Consanguineous families
What do endogenous opiates do?
- Inhibit GnRH at the hypothalamus (which in turn decreases FSH/LH release)
- Secreted in response to stress, these are the body’s “painkillers”
- Modified by estrogen/progesterone
- Modulate negative feedback of estrogen/progesterone on hypothalamic GnRH
Endogenous beta endorphin is 5-10x more/less potent than morphine
Beta endorphin is MORE potent than morphine
What are the 3 precursor peptides of endogenous opiates?
- POMC > endorphins
- Proenkephalin A and B > enkephalins
- Prodynorphin > dynorphins
POMC >
MSH, ACTH, Endorphins
The pituitary lies in the ___ of the ___ bone
Sella tursica of the sphenoid bone
What is GnRH self-priming?
In presence of estrogen, progesterone receptors activated/augmented»_space; eventually allows for even greater gonadotropin release in mid-cycle (storage of gonadotropin vesicles)
What gonadotropin is primarily secreted by a gonadotroph adenoma?
FSH (high)
LH (normal)
What is the rate-limiting step in gonadotropin synthesis?
Beta-subunit availability (GnRH dependent)
How does FSH create synergy in effecting LH surge?
Increases LH receptors
How is the pineal gland involved in puberty?
Increased darkness > increased melatonin > inhibits puberty
How does the ovary feedback on the pituitary?
Paracrine signaling:
Granulosa cells of the ovary:
- Inhibin –| inhibits FSH (only); may enhance LH
- Activin –> augments FSH secretion
How does the pituitary feedback on itself?
Autocrine signaling:
- Follistatin –| inhibits FSH
- Increases frequency of
What factors stimulate GnRH?
- Glutamine
- Kisspeptin
- Leptin
- Norephinephrine
- NPY (post-puberty, in the presence of estrogen)
What factors inhibit GnRH?
- GABA
- Dopamine, Serotonin
- Opioids, Endorphins
- NPY (pre-puberty, or whenever E2 is low; “brake” of puberty”
- Hyperprolactinemia
The short half-life of GnRH is due to rapid cleavage at aa __
5-6
6-7
9-10
*These are the sites of modifications for analogues
Mechanism by which:
- GnRH agonists work
- GnRH antagonists work
GnRH agonists: down-regulation
GnRH antagonists: competitive inhibition
Which receptor via which mechanism does dopamine inhibit prolactin?
D2 receptor
cAMP 2nd messenger system
What stimulates dopamine (and inhibits prolactin)
What inhibits dopamine (and stimulates prolactin)
- Prolactin
- Serotonin
- NPY
- Estrogen
- Endogenous opioids
- Psych drugs (risperidone)
*Newer psych drugs do not: e.g. olanzapine, quetiapine, aripiprizole
If normal prolactin + macroadenoma, check ___?
GH
IGF-1
Posterior pituitary hormones?
Vasopressin
Oxytocin
These are called neurophysins
Posterior pituitary is NOT an endocrine organ as it does not synthesize true hormones
Ablation of paraventricular nucleus causes ___ because of decreased ___
Hypernatremia
Vasopressin
Pre-puberty, GnRH is inhibited at the hypothalamus level due to
Changing levels of central inhibition of pulsatile GnRH secretion
High sensitivity to negative feedback by estrogen/LH (this is a lesser phenomenon)
GABA
NPY
At start of puberty, which hormone increases first? Why?
- FSH because GnRH frequency is slow!
- Nighttime LH pulses
When does LH start to rise > FSH pre-puberty?
8-12 years old
1 year prior to thelarche
Just before puberty, increase in ___ pulses
nighttime LH
In puberty, LH pulse frequency goes from ___ to ___
slow to fast
What is the juvenile pause?
Time between infancy > puberty
Which steroid hormone rises first in girls during puberty?
DHEA, DHEAS at 6-8 years old
When will menarche occur after puberty?
2.6 years
What can cause precocious puberty?
Black/hispanic
Obesity
Lives near equator
Blindness
Family history
Puberty sequence of events
- 6 yo - adrenarche (activation of adrenal androgens 2-3 years prior to puberty), increase in DHEAS in serum from zona reticularis of adrenal
- Growth spurt
- 10.5 yo - thelarche
- 11 yo - pubarche
—peak height velocity— - 12.8 yo - menarche
AG-BPM
What is the first visible sign of puberty?
Accelerated growth (even though adrenarche happens first)
Mutation responsible for Laron Dwarf
Growth hormone receptor mutation
“Short Larry broke the receptor”
GH from ___ –> ___ to secrete ___
Pituitary: GH –> liver: IGF-1
Define precocious puberty
Puberty at 6-8 yo (breast/pubarche)
Greater than 2.5 SD above average
What percentage of precocious puberty is caused by brain tumor?
10%
First step in evaluation of precocious puberty
Bone age
- if advanced, administer GnRH stim test to evaluate if HPO axis has been activated (LH high)
Precocious puberty ddx
- Gonadotropin-dependent: +GnRH stim test
- CNS tumor (hamartomas most common), infection, trauma, radiation
- Idiopathic (90%)
Tx: remove tumor if present, GnRH agonist to suppress - Gonadotropin-independent: - GnRH stim test
- Granulosa cell tumor > estrogen
- McCune Albright: constitutive activation of Galpha subunit of G protein coupled receptor
- Exogenous estrogen - Incomplete/Pseudo
- Isolated premature thelarche
- CAH
- PCOS
- Trauma/abuse, coagulopathy
Treatment for McCune Albright
Anastrozole (aromatase inhibitor)
If does not work, GnRH agonist
Ddx for delayed puberty
- Hypo hypo
- Karyotype
- Brain MRI for tumor
- Prolactin, TSH, DHEAS - Hyper hypo
- Karyotype
Is constitutional pubertal delay common in girls?
NO
First tests in evaluation of delayed puberty
- Bone age
- FSH, LH, E2
What is the Bayley-Pinneau table?
Predicts height
PIIGGOTS
“PIIGGOTS dont go to CAMP”
P - Prolactin (cytokine receptor, JAK-STAT)
I - Insulin, IGF-1 (tyrosine kinase receptor)
I - Inhibin (and Activin) (serine threonine kinase)
G - Growth hormone, veGF, eGF (tyrosine kinase)
G - GnRH (G protein PLC Gq)
O - Oxytocin (G protein PLC Gq)
T- TRH (G protein PLC Gq)
S - KiSspeptin (G protein PLC Gq)
Layers of adrenal cortex
“Gets better as you go in”
G - Salt (Mineralocorticoids)
F - Sweet (Glucocorticoids)
R - Sex (Steroids)
