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REI Written Boards 2024 - AK > Neuroendocrinology > Flashcards

Neuroendocrinology Flashcards

1
Q

Hypothalamic neurohormones
and their
Anterior pituitary hormones

A
  1. GnRH > FSH/LH (gonadotrophs)
  2. CRH > ACTH (& MSH) (corticotrophs)
  3. TRH > TSH (thyrotrophs)
  4. Dopamine –| Prolactin (lactotrophs)
  5. GHRH/Somatostatin > GH (somatotrophs)
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2
Q

Where is GnRH produced?

A

Hypothalamus (medial, basal; median eminence) - arcuate nucleus

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3
Q

Where do GnRH cells originate from?

A

Olfactory neurons

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4
Q

Anosmia
No puberty

A

Kallman syndrome

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5
Q

Pathophysiology behind Kallman syndrome

A

Failure of olfactory axonal and GnRH neuronal migration from the olfactory placode
- No GnRH
- No smell

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6
Q

Three mutations causing Kallman syndrome

A

Mutations in:

  1. KAL-1 gene, X-linked (increased frequency 5-7x in males): deficient cell adhesion and protease inhibition essential for neuronal migration
  2. FGFR-1 gene, AD or AR
  3. Abnormal tyrosine kinase receptors
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7
Q

GnRH precursor hormone –>

A

GnRH (decapeptide) + GAP (inhibits prolactin, stimulates gonadotropins)

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8
Q

What is the half-life of GnRH?

A

2-4 minutes

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9
Q

Discuss pathway of GnRH hormone release

A
  1. GnRH synthesis: median eminence/arcuate nucleus of hypothalamus
  2. GnRH transport down axon: GnRH tuberoinfundibular tract
  3. 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

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10
Q

Describe the different feedback loops

A

Long: estrogen/progesterone > hypothalamus and pituitary

Short: LH/FSH > hypothalamus

Ultra-Short: GnRH > hypothalamus (using dopamine, NE, endorphin, serotonin, melatonin)

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11
Q

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?

A

*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

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12
Q

Where is dopamine synthesized?

A

Arcuate and periventricular nucleus

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13
Q

What does dopamine do?

A

Dopamine suppresses prolactin

Prolactin suppresses GnRH release

(So dopamine normally functions to allow normal GnRH and gonadotropin release)

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14
Q

What does norepinephrine do?

A

Norepinephrine stimulates GnRH secretion in the presence of estrogen via neuropeptide Y (NPY)

NE in absence of estrogen inhibits GnRH secretion

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15
Q

What does neuropeptide Y (NPY) do?

A
  • 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)
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16
Q

What does kisspeptin do?

A
  • “First kiss” > then puberty
  • Initiates GnRH secretion at puberty if enough leptin
  • Regulated by estrogen/progesterone
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17
Q

What occurs with kisspeptin GPR54 mutations?

A

Hypo hypo > delayed puberty (decreased GnRH secretion)

Consanguineous families

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18
Q

What do endogenous opiates do?

A
  • 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
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19
Q

Endogenous beta endorphin is 5-10x more/less potent than morphine

A

Beta endorphin is MORE potent than morphine

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20
Q

What are the 3 precursor peptides of endogenous opiates?

A
  • POMC > endorphins
  • Proenkephalin A and B > enkephalins
  • Prodynorphin > dynorphins
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21
Q

POMC >

A

MSH, ACTH, Endorphins

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22
Q

The pituitary lies in the ___ of the ___ bone

A

Sella tursica of the sphenoid bone

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23
Q

What is GnRH self-priming?

A

In presence of estrogen, progesterone receptors activated/augmented&raquo_space; eventually allows for even greater gonadotropin release in mid-cycle (storage of gonadotropin vesicles)

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24
Q

What gonadotropin is primarily secreted by a gonadotroph adenoma?

A

FSH (high)
LH (normal)

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25
Q

What is the rate-limiting step in gonadotropin synthesis?

A

Beta-subunit availability (GnRH dependent)

26
Q

How does FSH create synergy in effecting LH surge?

A

Increases LH receptors

27
Q

How is the pineal gland involved in puberty?

A

Increased darkness > increased melatonin > inhibits puberty

28
Q

How does the ovary feedback on the pituitary?

A

Paracrine signaling:
Granulosa cells of the ovary:
- Inhibin –| inhibits FSH (only); may enhance LH
- Activin –> augments FSH secretion

29
Q

How does the pituitary feedback on itself?

A

Autocrine signaling:
- Follistatin –| inhibits FSH
- Increases frequency of

30
Q

What factors stimulate GnRH?

A
  • Glutamine
  • Kisspeptin
  • Leptin
  • Norephinephrine
  • NPY (post-puberty, in the presence of estrogen)
31
Q

What factors inhibit GnRH?

A
  • GABA
  • Dopamine, Serotonin
  • Opioids, Endorphins
  • NPY (pre-puberty, or whenever E2 is low; “brake” of puberty”
  • Hyperprolactinemia
32
Q

The short half-life of GnRH is due to rapid cleavage at aa __

A

5-6
6-7
9-10

*These are the sites of modifications for analogues

33
Q

Mechanism by which:
- GnRH agonists work
- GnRH antagonists work

A

GnRH agonists: down-regulation

GnRH antagonists: competitive inhibition

34
Q

Which receptor via which mechanism does dopamine inhibit prolactin?

A

D2 receptor
cAMP 2nd messenger system

35
Q

What stimulates dopamine (and inhibits prolactin)

What inhibits dopamine (and stimulates prolactin)

A
  • Prolactin
  • Serotonin
  • NPY
  • Estrogen
  • Endogenous opioids
  • Psych drugs (risperidone)
    *Newer psych drugs do not: e.g. olanzapine, quetiapine, aripiprizole
36
Q

If normal prolactin + macroadenoma, check ___?

A

GH
IGF-1

37
Q

Posterior pituitary hormones?

A

Vasopressin
Oxytocin

These are called neurophysins

Posterior pituitary is NOT an endocrine organ as it does not synthesize true hormones

38
Q

Ablation of paraventricular nucleus causes ___ because of decreased ___

A

Hypernatremia

Vasopressin

39
Q

Pre-puberty, GnRH is inhibited at the hypothalamus level due to

A

Changing levels of central inhibition of pulsatile GnRH secretion

High sensitivity to negative feedback by estrogen/LH (this is a lesser phenomenon)

GABA

NPY

40
Q

At start of puberty, which hormone increases first? Why?

A
  1. FSH because GnRH frequency is slow!
  2. Nighttime LH pulses
41
Q

When does LH start to rise > FSH pre-puberty?

A

8-12 years old
1 year prior to thelarche

42
Q

Just before puberty, increase in ___ pulses

A

nighttime LH

43
Q

In puberty, LH pulse frequency goes from ___ to ___

A

slow to fast

44
Q

What is the juvenile pause?

A

Time between infancy > puberty

45
Q

Which steroid hormone rises first in girls during puberty?

A

DHEA, DHEAS at 6-8 years old

46
Q

When will menarche occur after puberty?

A

2.6 years

47
Q

What can cause precocious puberty?

A

Black/hispanic
Obesity
Lives near equator
Blindness
Family history

48
Q

Puberty sequence of events

A
  1. 6 yo - adrenarche (activation of adrenal androgens 2-3 years prior to puberty), increase in DHEAS in serum from zona reticularis of adrenal
  2. Growth spurt
  3. 10.5 yo - thelarche
  4. 11 yo - pubarche
    —peak height velocity—
  5. 12.8 yo - menarche

AG-BPM

49
Q

What is the first visible sign of puberty?

A

Accelerated growth (even though adrenarche happens first)

50
Q

Mutation responsible for Laron Dwarf

A

Growth hormone receptor mutation
“Short Larry broke the receptor”

51
Q

GH from ___ –> ___ to secrete ___

A

Pituitary: GH –> liver: IGF-1

52
Q

Define precocious puberty

A

Puberty at 6-8 yo (breast/pubarche)
Greater than 2.5 SD above average

53
Q

What percentage of precocious puberty is caused by brain tumor?

A

10%

54
Q

First step in evaluation of precocious puberty

A

Bone age
- if advanced, administer GnRH stim test to evaluate if HPO axis has been activated (LH high)

55
Q

Precocious puberty ddx

A
  1. Gonadotropin-dependent: +GnRH stim test
    - CNS tumor (hamartomas most common), infection, trauma, radiation
    - Idiopathic (90%)
    Tx: remove tumor if present, GnRH agonist to suppress
  2. Gonadotropin-independent: - GnRH stim test
    - Granulosa cell tumor > estrogen
    - McCune Albright: constitutive activation of Galpha subunit of G protein coupled receptor
    - Exogenous estrogen
  3. Incomplete/Pseudo
    - Isolated premature thelarche
    - CAH
    - PCOS
    - Trauma/abuse, coagulopathy
56
Q

Treatment for McCune Albright

A

Anastrozole (aromatase inhibitor)
If does not work, GnRH agonist

57
Q

Ddx for delayed puberty

A
  1. Hypo hypo
    - Karyotype
    - Brain MRI for tumor
    - Prolactin, TSH, DHEAS
  2. Hyper hypo
    - Karyotype
58
Q

Is constitutional pubertal delay common in girls?

A

NO

59
Q

First tests in evaluation of delayed puberty

A
  • Bone age
  • FSH, LH, E2
60
Q

What is the Bayley-Pinneau table?

A

Predicts height

61
Q

PIIGGOTS

A

“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)

62
Q

Layers of adrenal cortex

A

“Gets better as you go in”

G - Salt (Mineralocorticoids)
F - Sweet (Glucocorticoids)
R - Sex (Steroids)

REI Written Boards 2024 - AK (25 decks)

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