Neuroendocrinology Flashcards
1
Q
Name the nuclei of the hypothalamus
A
supraoptic, preoptic, paraventricular, ventromedial, arcuate, suprachiasmatic
2
Q
Function of preoptic nucleus
A
Thermoregulation, contained GnRH neurons
3
Q
Paraventricular nucleus secretes
A
Oxytocin, vasopressin/ADH, CRH and TRH
4
Q
Loss of vasopressin leads to
A
Diabetes insipidus and hypernatremia
5
Q
Continuous vasopressin secression leads to
A
SIADH and hyponatremia
6
Q
Function and product of ventromedial nucleus
A
Feeding, fear, thermoregulation, and sexual activitiy Secretes oxycotocin (inhibits appetite, stimulates sexual behavior)
7
Q
Arcuate nucleus secretes
A
GnRH, POMC, NPY, GHRH, kisspeptin, dopamine
8
Q
Suprachiasmatic nucleus controls
A
Circadian rhythms
9
Q
Suprachiasmatic nucleus location
A
Above optic chiasm
10
Q
What are neurophysins at what do they do?
A
Carrier proteins which transport the hormones oxytocin (NP1) and vasopressin (NP2) to the posterior pituitary from the paraventricular and supraoptic nucleus of the hypothalamus
11
Q
Location of genes for neurophysin 1/2
A
Chromosome 20
12
Q
Location of GnRH and other factor release into portal system for delivery to anterior pituitary
A
Median eminence
13
Q
Location of median eminence
A
Base of the third ventricle
14
Q
Internal zone of median eminence contains:
A
Lined with tanycytes (ependymal cells), contains portal capillary loops and fibers of supraopticohypophysial tract
15
Q
External zone of median eminence contains:
A
fibers from parvocellular neurons throughout forebrain
16
Q
Long feedback loop
A
Effect of circulating levels of target gland hormones on the hypothalamus and pituitary
17
Q
Short feedback loop
A
Negative feedback of pituitary hormones on their own secretion by inhibitory effects of hypothalamic releasing hormones [retrograde flow in portal system]
18
Q
Ultrashort feedback loop
A
Inhibition by the releasing hormone on its own synthesis
19
Q
AAs in GnRH
A
10
20
Q
AAs in TRH
A
3
21
Q
AAs in oxyctocin
A
9
22
Q
Stimulatory feedback on GnRH
A
- Norepi
- Glutamate
- NPY (only in presence of estrogen)
- Kisspeptins
- Oxytocin (inhibits degradation enzymes)
- activin (stimulates GnRH-R)
23
Q
Inhibitory feedback on GnRH
A
- Dopamine
- serotonin
- opioids (beta-endorphin and dynorphin)
- CRH
- melatonin
- PRL
- GABA
24
Q
GnRH pulsatility in follicular and luteal phases
A
Follicular phase: High frequency, low amplitude -> LH
Luteal phase: Low frequency, high amplitude -> FSH
25
Kallman's syndrome pathogenesis
Failure of olfactory and GnRH neuronal migration from olfactory placode
26
Kallman's syndrom mutations (2)
• X-linked (most common): Anosmin 1
Encoded by KAL gene on X chromosome (short arm)
Part of fibronectin family, responsible for cell adhesion and protease inhibition
• Autosomal:
Fibroblast growth factor receptor (FGF-1 R) and prokinecticin
Both autosomal recessive and autosomal dominant forms
27
GnRH agonist substitution
Sub of Gly at position 6 or replacing C-termin glycine-amine which inhibits degradation
28
GnRH agonist response
Initially due to desensitization (uncoupling of receptor for effector system)
Sustained response 2/2 loss of receptors by downregulation and internalization
29
GnRH antagonist molecular change
Multiple amino acid subs
30
GnRH antagonist function
Bind to GnRH receptor and competitively inhibit endogenous GnRH
31
Pituitary somatotropes: % and product
50%, GH
32
Pituitary lactotropes: % and product
10-25%, PRL
33
PItuiitary corticotropes: % and product
10-20%, Pro-opiomelanocortin (POMC) --\> cleaves to ACTH, beta-lipotropin, and MSH
34
Pituitary thyrotropes: % and product
10%, TSH
35
Pituitary gonadotropes: % and product
10%, FSH/LH
36
Most common deficiencies in hypopituitarism
PRL and GH
| (next most common: gonadotropins \> ACTH \> TSH)
37
LH pulse freq throughout menstrual cycle
* Early follicular phase – q 90 minutes
* Late follicular phase – q 60-70 minutes (highest preparing for pre-ovulatory surge)
* Early luteal phase – q 100 minutes
* Late luteal phase – q200 minutes (slowest preparing for luteal rise in FSH)
38
Male LH deficiency dx and tx
dx: measure testosterone
tx: testosterone replacement if secondary hypogonadism and not interested in fertility
39
Female LH deficiency dx and tx
dx: measure FSH/LH/E2, progesterone withdrawal
tx: E2/P4 replacement if not interested in fertility
40
ACTH deficiency test/results
AM serum cortisol
• ≤ 3 mcg/dL, confirms low ACTH
• ≥ 18 mcg/dL, ACTH secretion is adequate
• In between, do ACTH reserve test
41
ACTH reserve tests (3)
Metyrapone test, insulin-induced hypoglycemia test, cosyntropin stim test
42
Metyrapone test
What does it block? and what should increase if normal?
Blocks 11β-hydroxylase (CYP11B1) which converts 11-deoxycortisol to cortisol, should cause increase in ACTH and increase in steroidogenesis
- Normal: Decline in AM serum cortisol \< 5mcg/dL (demonstrates metyrapone adequately blocking) and 8AM 11-deoxycortisol concentration 7-22 mcg/dL
- Abnormal: 11-deoxycortisol \< 7 mcg/dL + suppressed cortisol
43
Insulin-induced hypoglycemia test
Hypoglycemia induced by insulin is sufficient stress to stimulate ACTH and therefore cortisol
Normal: Cortisol ≥ 18 mcg/dL and glucose \< 50 mg/dL after 120 min
44
Cosyntropin stim test
Adrenal glands atrophy when not stimulated in prolonged period so do not secrete cortisol in response to ACTH
Normal: serum cortisol ≥ 18 mcg/dL after 60 minutes
45
Tx ACTH deficiency
hydrocortisone rx (cortisol replacement) --\> note: may unmask diaBetes insipidus
46
Prolactin forms (3) and size
o Monomeric (23 kDa) – most biologically active (80-90%)
o Dimers/trimers (50-60 kDa) – less biologically active (big prolactin)
o Large polymers (\>100kDa) – less biologically active
47
PRL feedback regulator
Pit-1 (regulated by PROP-1) - most likely cause of hypo/hypo
48
Stimulatory feedback to PRL
* TRH, VIP, EGF, GnRH, GHRH
* Estrogen and opioids act via inhibition of dopamine
* Demonstrated in vitro: growth factors, Angiotensin II, vasopressin
* Medications: phenothiazines, amphetamines, reserpine, opiates, alpha methyl dopa, butyrophenones, TCAs, metoclopramide (dopamine antagonist)
**NOT diazepams at normal doses**
49
Inhibitory feedback to PRL (5)
* Prolactin itself (primary, via dopaminergic system)
* Dopamine (via receptor that inhibits G-protein/cAMP activity)
* GABA
* NPY (via inhibition of dopamine)
* Serotonin
50
Etiologies of hyperprolactinemia
• Physiologic – exercise, lactation, pregnancy, sleep, stress
• Pharmacologic – see above
• Pathologic:
• Hypothalamic-pituitary stalk damage (i.e. radiation, trauma, tumors)
• Pituitary (i.e. prolactinoma, GH-secreting tumor, macroadenoma)
~10% of adenomas that secrete prolactin also secrete GH, leading some to recommend measuring the serum IGF-1 concentrations, even in women with microadenomas
25-40% of GH-secreting tumors secrete PRL
• Systemic disorders (i.e. cirrhosis, renal failure, Cushing’s)
51
Mechanism of hyper-PRL induced amenorrhea
Hyperprolactinemia inhibits pulsatile hypothalamic GnRH secretion, resulting in decreased levels of pituitary FSH and LH secretion (no galactorrhea bc low estrogen due to low gonadotropins)
52
Tx hyperprolactinemia induced amenorrhea
* Desires fertility: Bromocriptine vs cabergoline
* Not trying to conceive: OCPs
53
Sequelae of PRL deficiency
Inability to lactate
54
GH deficiency testing
o Test: Measure IGF-1 and/or do provocative test (insulin-induced hypoglycemia or arginine/GHRH)
o For insurance coverage, must have:
• low IGF-1 concentration or poor GH response to two standard stimuli, and
• hypopituitarism due to pituitary or hypothalamic damage
55
GH deficiency effects in adult
unfavorable serum lipid profiles, increased body fat, decreased muscle mass, decreased BMD, diminished sense of well-being
56
How does nitrous oxide synthase stimulate GnRH release? (cellular mechanism)
via activation of guanylyl cyclase to generate cGMP as 2nd messenger
57
What increases the production of NO?
Estrogen – thus contributing to the positive feedback of estrogen on GnRH in the mid-cycle
58
* breakdown point of GnRH?
* How is GnRH changed in agonists & antagonists?
* Position 6 (glycine)
* Agonist - Replacement of the glycine at position 6 by D-amino acids
* Antagonist - Multiple amino acid substitutions including replacement of the glycine at position 6 by D-amino acids
59
Mechanism of GnRH-agonist therapy
Desensitization → down-regulation
60
Diurnal variation in LH/FSH
* LH (and FSH) exhibit **nocturnal decline –** probably mediated by endogenous opiates
* **LH** has nocturnal decline **only in early follicular phase**
* **FSH** has nocturnal decline **throughout cycle** – mediated by endogenous opiates
61
Recombinant FSH & LH
How are they different?
Same strength?
1. differs from native product in regards to glycosylation pattern
2. rFSH is the same, rLH is lower
62
Breakdown products of proopiomelanocortin (POMC)
* Β-endorphin
* ACTH
* Melanocyte-stimulating hormone (MSH)
63
How do β-endorphins change in menstrual cycle?
* Highest during luteal phase
* Peaks with FSH/LH peak
* Nadirs with menses
64
What happens if β-endorphins are infused?
* Increase in glucagon
* Suppress GnRH release
* No change in ACTH, GH, insulin or cortisol levels
65
Melatonin comes from? produced by? increased levels in response to…?
* Tryptophan → 5HTP → Serotonin → NAS → melatonin
* Melatonin is produced by the pineal gland
* Generated in a circadian pattern – increased levels in response to darkness
66
**Diurnal variation in pituitary hormones**
Nighttime rise in:
* ACTH
* TSH
* GH
* Prolactin
Nighttime drop in:
* FSH
* LH
67
What is the result of pituitary stalk transection?
* Increased prolactin
* Decreased ADH → diabetes insipidus
* Anterior pituitary hormones decrease to basal levels – anterior pituitary continues to get some blood supply via the inferior hypophyseal artery
68
What does NOT occur in panhypopit?
Does NOT cause hyperpigmentation or salt wasting because it doesn’t affect aldosterone secretion
69
Hormones needed to treat panhypopit?
* ACTH
* FSH/LH
* GH
* TSH
70
Categories of hyperprolactinemia
* Mild (20-50 ng/mL) – short luteal phase
* Moderate (50-100 ng/mL) – oligomenorrhea, amenorrhea
* Severe (\>100 ng/mL) – frank hypogonadism (osteopenia, genital atrophy), low E2 levels
71
With prolactinoma, what hormone abnormalities are you likely to see?
* Elevated GH
* Decreased FSH/LH
* Decreased GnRH
* Elevated prolactin
72
Medications associated with hyperprolactinemia
* Antipsychotic drugs – dopamine **D2-receptor antagonists**
* Gastric motility drugs
* Antihypertensives
* H2-blockers
* Amphetamines
* Opiates
73
what % of pituitary macroadenomas are also gonadotroph adenomas?
40-50%
74
Which conditions are associated with growth hormone deficiency?
* Delayed puberty
* Micropenis
* Hypoglycemia
* Exaggerated jaundice
* Holoprosencephaly (panhypopitutarism)
* Craniopharyngioma
* Histiocytosis X
75
Which conditions are associated with growth hormone excess?
* Acromegaly
* Giantism
* Laron syndrome (AR, GH receptor defect, results in dwarfism)
76
Does GH deficiency always result in reproductive issues? and which ones?
No
menstrual cycle abnormalities, subfertility
77
Treatment for a woman with recurrent acromegaly after repeated surgical resections?
* Somatostatin analog (Octreotide) (first line)
* Dopamine agonists (cabergolin, bromocriptine)
* GH receptor antagonist (Pegvisomant)
78
Most likely endocrinopathies s/p transphenoidal resection in someone with acromegaly?
* Posterior pit - ADH deficiency – diabetes insipidus (18-31%)
* Anterior pituitary hormone deficiencies
1. GH deficiency – 83% (overcorrection)
2. LH/FSH – 60%
3. TSH – 30%
4. ACTH – 30%
79
Endocrine profile of craniopharyngioma (aka Rathke pouch tumor)
1. Decreased GH, FSH/LH, TSH, ACTH **(in order of decreasing frequency)**
2. Decreased ADH (diabetes insipidus) **(due to pituitary stalk compression**)
3. Increased prolactin **(due to pituitary stalk compression)**
4. Increased hypothalamic hormones (GnRH, CRH, GHRH, TRH) if target cells in pituitary destroyed
80
What gives you hypercarotinemia?
* Anorexia (hypothalamic amenorrhea)
* Hypothyroidism
* Diabetes
* Liver disease
* Nephrotic syndrome
* Increased intake of carotenoids
81
Empty sella syndrome s/sx
1. Headache
2. Galactorrhea
3. Irregular menses
4. mild hyperprolactinemia
82
Characteristics of Craniopharyngiomas on XR?
calcium deposits
83
Characteristics of Hamartoma?
Heterotopic neuronal masses containing GnRH neurons
ectopic GnRH pulse generator
Most common tumor associated with precocious puberty
Associated with gelastic seizures (laughing, giggling)
