Pituitary, Receptors, ADH Flashcards
1
Q
Order of acquired loss of anterior pituitary function
A
GH, LH/FSH, TSH, ACTH, and PRL.
Go look for the anterior pituitary
Go look for the adenoma please
2
Q
Causes of hypopituitarism
A
9 I’s
Invasic
Idiopathic
Infection
Infiltrative
Infarction
Injury
Immunologic
Iatrogenic
Isolated
3
Q
Hypothalamus comes from what 2 neurons
A
Hypophyseotropic neurons
PVN & Arcuate N
(ant pit)
Magnocellular neurons
PVN and SON
(post pit)
4
Q
how is ant pit formed
A
Invagination of Rathke’s Pouch (ectoderm)
5
Q
what is Pars Intermedia
A
boundary between anterior & posterior – remnant of Rathke’s Pouch
6
Q
how is post pit formed
A
Invagination of ventral HT & 3rd ventricle
(ectoderm)
7
Q
what ant pit hormones DO NOT bind to Protein coupled receptor
A
Growth hormone
Prolactin
8
Q
what simulates/inhibits GH
A
GHRH stimulates
somatostatin inhibits
9
Q
what simulates/inhibits TSH
A
TRH stimulates
somatostatin inhibits
10
Q
what simulates/inhibits PRL
A
dopamin inhibits
TRH and Oxytocin stimulate
11
Q
what simulates/inhibits ACTH
A
CRH and AVP stimulate
12
Q
what does TRH simulate
A
TSH
PRL
13
Q
what does somatostatin inhibit
A
GH
TSH
14
Q
what does dopamine inhibit
A
PRL
15
Q
what kind of hormones are TRH, CRH, GHRH, GnRH
A
peptides
16
Q
what kind of hormones are the following hormones:
ACTH:
LH, FSH, TSH:
GH, PRL:
A
ACTH: Peptide
LH, FSH, TSH: Glycoproteins
GH, PRL: Protein
17
Q
in GPCR what does Gsα do
A
stimulates AC, makes PKA
Adenyl cyclase
Protein kinase A
18
Q
in GPCR what does Gqα do
A
stimulates PLPC, makes PKC
Phospholipase C
Protein kinase C
19
Q
what hormones bind to Gsα
A
CRH
ACTH
TSH
GHRH
LH,FSH
CaSR
PTH
20
Q
what hormones bind to Gqα
A
TRH
GnRH
GHS-R
AVP (1b)
Oxy
21
Q
in GPCR what does Giα do
A
inhibits Adenyl cyclase
22
Q
what stimulates GH
A
Hormones:
GHRH
Ghrelin
Thyroid hormone
Estrogen
Dopamine (L-Dopa)
Glucocorticoids
Nutrition
Fasting
Hypoglycemia
- Glucagon
- Insulin
Protein/amino acids
- Arginine
Malnourished
Other:
Galanin
Alpha agonists (Clonidine)
Beta antagonists (Propranolol)
Exercise
Stress
Trauma
Sepsis
23
Q
What inhibits GH secretion
A
Hormones:
SRIF
IGF-1
Hypothyroidism
Hyperthyroidism
Glucocorticoids
Chronic admin
Deficiency
Nutrition:
Glucose
FFA
Other:
Depression
Emotional deprivation
β-adrenergy
24
Q
what hormones share a common Alpha unit and have a specific beta unit
A
TSH
LH
FSH
HCG
CαSβ
Common Alpha
Specific Beta
Rock the Casbah
25
How does TSH work at receptor
Binds GPCR (Gsα) - PKA
This increases:
- Iodide influx into cell, efflux into colloid
- Synthesis of
---NADPH
---Hydrogen Peroxide
---Thyroglobulin (TG)
---TPO
-Uptake of TG into cell, release into plasma
26
What stimulates TSH
TRH
Low T3
Leptin
27
What are TSH Inhibitors
SRIF
T3
Glucocorticoids
Dopamine (acutely)
Fasting/Starvation
Certain cytokines
28
Important genes for GnRH
KAL1
PROK2
FGF8
FGFR1
PROKR2
NELF
CHD7
WDR11
HS6ST1
SEMA3A
29
What stimulates the release of GnRH
Stimulate release:
Leptin (LEP/LEPR)
Kisspeptin (KISS1/GPR54)
PC1
Norepinephrine
Glutamate
30
what inhibits the release of GnRH
GABA
MKRN3
Opiate R
Estrogen
Through KISS1R
Progesterone
Decrease pulses
Testosterone
Through KISS1R
No E required
31
PRL is Stimulated by?
TRH
T4, T3
Estradiol
VIP
FGF, EGF
Serotonin
GHRH (GHRH tumors – higher PRL)
32
PRL is inhibited by?
Dopamine
Prolactin
33
What is PRL role
Important in pregnancy
-Mammary
- Lactation if suckling
- No milk during pregnancy
Not primary for milk ejection
Oxytocin
Inhibits LH, FSH
(Secondary amenorrhea while breast feed)
- Inhibit Kisspeptin
34
what stimulates vasopressin
Osmolality >> Volume > Pressure
1% increase in Osm = AVP release
10-fold higher required for V/P
Pain, nausea = stimulation
- Glutamate
35
Triple phase response to surgery/trauma
phases and lengths
DI
- Edema, “stunning”
- 12 hours – Few days
SIADH
- Necrosis, release AVP
- May last up to 2 weeks
DI
- Cell death
- Indefinite
Some don't have the first phase and just start with SIADH
36
what are pathologic causes of high prolactin
Prolactinoma (> 1000ug/dl)
Stalk Compression/dissection
Hypothyroidism
Surgery
Seizure
Head Trauma
Renal Failure
Hypothalamic mass
Prolactin receptor mutation
37
what are physiologic causes of high prolactin
Pregnancy
Lactation
Stress
Coitus
Nipple stimulation
Sleep
Exercise
38
what drugs can cause high prolactin
Dopamine antagonists (Parkinson meds)
Antipsychotics: Risperidone
Estrogen
Ranitidine
Anti epileptics: Phenytoin
Opiates
Anti depression: SSRIs, TCAs
39
what is the cutoff for prolactinoma
>200 ug/L
40
what syndrome to think of with prolactinoma
MEN1
41
What's the most common presenting sx of prolactinoma
hypogonadism
42
What workup should you do for hyperPRL
TFTs
Macroprolactin (less bioactive)
43
treatment for hyperPRL
Dopa agonist
Bromocriptine
Cabergoline
OCP
44
most common tumours affecting pituitary
1) craniopharyngioma
2) pituitary adenoma
germinoma
45
craniopharyngioma
- what is it
- benign /maglinant
- remnant of Rathke pouch
- sellar tumour
- benign tissue but mass affect causes a lot of problems
most common type: Adamantinomatous
46
Pituitary adenoma - most common pit def
PRL
ACTH
47
Germinoma
most common association?
DI because of stalk
DI most common, followed by growth, puberty (may be precocious)
48
Hypopituitarism following cranial XRT
Less than what is def unlikely?
Above what is def very likely?
what are other cutoffs?
<10 Gy
>50 Gy
≥22 Gy: GH, LH, FSH
≥30 Gy: TSH, ACTH
49
What are infiltrative causes of hypo pit?
Sarcoidosis
LCH
50
What are inflammatory causes of hypo pit?
Inflammatory:
Lymphocytic hypophysitis (autoimmune)
51
How does undernutrition affect HP axes?
↑GH ↓IGF-1
↓ LH/FSH, ↓T,E
↑CRH, ↑ACTH, ↑Cortisol
↓ TSH, ↓ T4,T3, ↑rT3
↑AVP; ↑Ghrelin; ↓Leptin
52
How does obesity affect HP axes?
↓ GH, Nl/low IGF-1 (↓ IGFBP1)
F: ↑LH/FSH ↓SHBG
M: ↓ LH/FSH ↓SHBG
↑24h UFC
↑11βHSD-1: ↑tissue cortisol
↑TSH (~5-10) ↑T3; T4
↑Leptin; Ghrelin: no↓
53
what will Unmask central AI
T4
GH
54
what will Unmask central DI
Cortisol
T4
55
what will Increase GH release, response
T4
Estradiol, Testosterone
56
where does vasopressin work and what does it do
acts on V2 receptors in principal cells in the collecting duct to stimulate the expression of intracellular water channels, aquaporin-2
57
what is the posterior pituitary
not a gland but only the distal axon terminals of the hypothalamic magnocellular neurons that make up the neurohypophysis
58
what deficiencies decrease water excretion
Hypothyroidism and adrenal insufficiency
when present may mask diabetes insipidus
59
water deprivation test - how does it work
NPO overnight
on arrival:
- if dehydrated with high urine Osm - test over
- check weight, serum Na, serum Osm
- volume and osmolality of each voided urine is recorded
- measure weight
60
how to end water de test
- give desmopressin
End by measuring:
Weight, vital signs
Plasma sodium, plasma and urine osmolality, and urine specific gravity
Obtain specimen for plasma ADH (HH in children with nephrogenic DI)
61
etiologies of SIADH
Ectopic production of vasopressin by cancer
- small cell lung ca
- squamous cell carcinoma
- cancers of head and neck
Drug-induced SIADH
Disrupt neural pathways
- pulmonary disorders (pneumonia, TB, fungal infection, empyema, positive pressure ventilation)
- CNS disorders (tumour, infection, trauma, surgery, hemorrhage, inflammatory diseases)
AIDS
Marathon running or other strenuous exercise
Acute psychosis
Nephrogenic SIADH(extremely rare mutation of the V2 receptor producing chronic activation)
62
criteria for SIADH
1) decreased plasma osmolality;
2) inappropriate concentration of the urine;
3) clinical euvolemia;
4) increased urinary sodium excretion;
5) and absence of other causes of euvolemic hypo-osmolality such as hypothyroidism, adrenal insufficiency, or diuretic use.
63
what drugs cause SIADH
Desmopressin
Oxytocin
Anticonvulsants:
- Carbamazepine
- Valproic acid
- Lamotrigine
Chemo
- vincristine
- cyclophosphamide
- cisplatin
- ifosfamide
- methotrexate
Opiates
Ecstasy
SSRI
Tricyclic antidepressants
Monoamine oxidase inhibitors
Clofibrate
Chlorpropamide
NSAIDS
Nicotine
Amiodarone
64
what are genetic causes of DI
V2 receptor mutation - Xlinked
Aquaporin-2 mutations – AR (can be AD)
65
Atrial Natriuretic Peptide - what does it do
- where is it releases
- stimuli
Inhibits Aldosterone Secretion
Atria
increased volume,
increased Na,
neurologic inputs
66
indications to end a water dep test
Urine osm >600 OR SG >1.020
Serum osm >300 OR Na >145
Wt. loss >5% bodyweight
Signs of volume depletion
Age appropriate period of water restriction exceeds rec’d max (6h<6mo, 8h <2y, 12h)
Central DI: a significant increase in urine osmolality to administered desmopressin
15-50%: partial DI
>100%: complete central DI
67
Meds that Cause of nephrogenic DI
-Lithium (interfere with vasopressin-induced cAMP generation or action)
-Demeclocycline (interfere with vasopressin-induced cAMP generation or action)
-Amphotericin B
- ifosphamide
- orlistat
68
non-pharm causes of nephrogenic DI
- Congenital X-linked DI: V2 receptor mutations
- Congenital Autosomal Nephrogenic DI: Aquaporin 2 Mutations
- Hypercalcemia
- Hypokalemia
- Ureteral Obstruction
- PKD
- Medullary cystic disease
- Sjogren Syndrome
- Sickle cell disease
- Bardet-Biedl (due to progressive CKD)
- Bartter syndrome
69
Ddx polyuria
i. Central diabetes insipidus
1. Inherited: Vasopressin gene mutation (x-linked) or AR syndromic (Wolfram/DIDMOAD)
2. Infiltrative
3. Infectious
4. Trauma
5. Autoimmune/idiopathic
ii. Inherited nephrogenic diabetes insipidus (aquaporin 2 channel mutation or vasopressin 2 receptor mutation): resistance to vasopressin at the kidney
iii. Lithium: causes resistance to vasopressin in the kidney
iv. Pregnancy induced diabetes insipidus: extra vasopressin degradation enzyme present in the placenta
v. Hypercalcemia: Causes resistance to vasopressin
vi. Hyperuremia: Causes diuresis to clear the urea
vii. Primary polydipsia: excess water intake
viii. Diuretic abuse
ix. diabetes mellitus
70
where are the V2 receptors
collecting duct of kidneys
71
what will you see with DDAVP in water dec test with nephrogenic DI vs central DI
i. Nephrotic DI – urine osm <300 mOsm/kg and does not increase by >50% after DDAVP
ii. Complete central DI – urine osm increase by >50% after DDAVP
72
tests for DI
i. Water deprivation test
ii. Copeptin measurement after hypertonic saline administration
iii. Hypertonic saline administration (looking for urine concentration afterwards)
73
List 2 genetic causes of NDI and their inheritance pattern
i. Vasopressin V2 receptor mutation – X-linked
ii. aquaporin-2 mutation – AR or AD
74
how to treat nephrogenic DI
i. Hydrochlorothiazide – causes natriuresis which produces some contraction of extracellular fluid volume, decrease GFR, decreased delivery of fluid to the collecting duct, and a decreased urine volume
ii. Indomethacin - has antidiuretic action that especially prolongs the action of vasopressin and administered DDAVP, it also decrease urine volume
75
causes of infundibulum enlargement?
=pituitary stalk lesion
- Langerhans cell histiocytosis
- Lymphocytic hypophysitis
- ectopic neurohypophysis
- Rathke cleft cyst
- Pituitary adenoma
- Craniopahryngioma
- germinoma
- astrocytoma
- metastatic lymphoma
- neurosarcoidosis
-
76
Anorexia nervosa - H-P effects
● Gonadal axis – low energy state resulting in hypothalamic amenorrhea (low LH/FSH)
○ Also have low androgen as well as estrogen
● Adrenal axis – chronically stimulated
○ hypercortisolemia
● Thyroid axis – nonthyroidal illness syndrome
○ Low total T3, high rT3 (due to increased peripheral deiodination of T4 to reverse T3)
○ Level of fT4 vary from normal to low-normal
○ TSH varies from normal to low-normal
● Growth – GH resistance due to chronic nutritional deprivation
○ GH high, Low IGF-1
i) Decreased BMD
ii) Hypoglycemia and hyperinsulin
- decreased leptin
77
Causes of high prolactin
i) Pituitary adenoma: excess prolactin secreted from adenoma
iI) Primary hypothyroidism: TRH stimulates prolactin release
iii) Chronic renal failure and hepatic failure: impairied prolactin degradation and impaired central regulation
iv) Chest wall trauma: Neurologic mechanism, likely similar to suckling
v) Pituitary stalk trauma (tumour, TBI, LCH, acromegaly (other pituitary mass) etc.): when the pituitary stalk is damaged there is no longer dopamine from the hypothalamus coming in to inhibit prolactin release
vi) Macroprolactinemia: due to antibodies causing a large prolactin aggregate, which is not active so has no symptoms, but only increases bound prolactin
vii) Dopamine receptor blockers (metoclopramide, antipsychotics): stops dopamine from inhibiting prolactin release
viii) Estrogen: binds to estrogen receptor (response element) that controls the prolactin gene in the lactotrophs
ix) Pregnancy: increases estrogen
78
pituitary adenoma - post op PRL goes up - what kind of tumour?
prolactinoma!!
b) What explains the pre-op and post-op findings?
Hook effect
c) What would you do to confirm the diagnosis?
Serial dilution
79
Cause of hypogonadotropic hypogonadism
i) CNS tumors
ii) Genetic defects – see below
iii) Syndromes – PWS, Bardet-Biedl, CHARGE
iv) Midline defects – SOD, congenital hypopit
v) Chemotherapy or radiation
vi) Trauma
vii) Systemic illness – IBD, celiac, anorexia nervosa, bulimia, sickle cell, hemosiderosis, asthma, CF
viii) Endocrinopathies – DM, GH deficiency, Cushing syndrome
ix) Excessive exercise
x) Malnutrition
xi) post CNS infection
80
single gene that can cause hypogonadotropic hypogonadism
i) Kallmann syndrome – KAL1, FGFR1
ii) Isolated hypogonadotropic hypogonadism – KAL1, GNRHR, GNRH1
iii) HPG Axis Development – DAX1, SF-1, HESX-1, LHX3, and PROP-1
iv) Obesity and hypogonadotropic hypogonadism - LEP, LEPR
81
syndromes that can cause hypogonadotropic hypogonadism
Prader Willi
Bardet Biedl
CHARGE
82
causes of function hypogonadotropic hypogonadism
systemic illness
- CF
- asthma
- IBD
- Celiac disease
- JA
- AN/ED
- Sickel cell
- Thalasemia
- Renal disease
endocrinopathies
- DM
- hypothyoidism
- hyperprolactinemia
- GHD
- Cushing
excess exercise
malnutrition
83
adv/disadv for carbegoline
side effects
● Advantages: only administered once or twice a week, higher rates of success suppressing prolactin
● Disadvantage: risk of valvular heart disease, only at high doses used in Parkinson’s
-nausea
-vomiting
-heartburn
-dizziness
-dysmenorrhea
-fatigue
-constipation
-orthostatic hypotension
-fibrotic valvulopathy
-psychiatric disturbances (esp impulse control disorders)
84
adv/disadv for bromocryptine
side effects
● Advantage: reduces adenoma size effectively
● Disadvantage: nausea (++), no as effective at lowering prolactin levels as cabergoline, given twice daily
-nausea
-orthostatic hypotension
-headache
-diarrhea
-abdominal pain
-anorexia
-fibrotic valvulopathy
-psychiatric disturbances (esp impulse control disorders)
85
MRI features of neurodevelopmental problems that can cause pituitary deficiencies
i) Absent posterior pituitary
ii) Optic nerve hypoplasia
iii) Ectopic posterior pituitary
iv) Small anterior pituitary
v) Thin pituitary stalk
vi) Absent corpus callosum or septum pellucidum
vii) Holoprosencephaly
viii) Schizencephaly
ix) Cerebellar hypoplasia
x) Chiari malformation
xi) Empty sella
86
features of SOD
optic nerve hypoplasia,
pituitary gland hypoplasia
midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum
87
reasons to consider transphenoidal surgery in adenoma
-Resistant to treatment (ie prolactin not coming down)
-macroprolactinomas with no tumour shrinkage with treatment and/or cannot tolerate dopamine agonist therapy consider pre-pregnancy resection
-Cannot tolerate medications (++ side effects)
-compressive symptoms
88
what kind of med is carbergoline
dopaminergic
89
What is the first line treatment of hyper PRL?
Dopamine agonist therapy
90
When considering stopping dopaminergic therapy what factors to consider?
○ Prolactin - needs to be normal
○ Duration of therapy - 2 years min
○ MRI finding - no evidence of adenoma
○ Initial prolactin level - the higher the PRL, the lower the chance of remission
○ Size of adenoma
○ Persistently symptomatic
○ Previously failed wean of therapy
○ (Menopause)
91
during pregnancy, what is the risk of increase in macroprolactinomas and microprolactinomas?
Risk of increase in microprolactinomas is 31% in pregnancy
Risk of increase in microprolactinomas is <5% in pregnancy
92
what is most common deficiency with holoprosencephaly
DI - 70% of individuals with holoprosencephaly have DI
Anterior pituitary deficiencies are less common
93
after cranio tx, what is most likely H def, and how does it present?
growth hormone deficiency
normally presents with normal growth velocity and excess weight gain
The treatment of GH deficiency does not cause improved final height, since growth velocity is normal, but can help with weight loss and improving lean muscle mass.
94
liver finding seen in hypopit
giant cell hepatitis
95
G protein inactivating mutation syndromes
2. Pseudohypoparathyroidism type 1a (maternally inherited) and AHO (paternally inherited): inactivating
3. Pseudohypoparathyroidism type 1b: inactivating
4. Jansen metaphyseal chondrodysplasia: activating (PTH receptor)
5. Blomstrand chondrodysplasia: inactivating (PTH receptor)
6. Kallman Syndrome: inactivating (prokinectin receptor 2)
7. Nephrogenic DI: inactivating (Vasopressin 2)
8. Familial benign hypocalciuric hypercalcemia/severe neonatal primary hyperparathyroidism (if homozygous): inactivating (CaSR)
9. Familial hypocalcemic hypercalciuria: activating (CaSR)
96
what hormone receptor is a nuclear receptor
where is it located
thyroid hormone receptor
on the nucleus
97
what kind of receptor does GH bind to
d) JAK-STAT/Cytokine
98
what hormones bind to a tyrosine kinase receptor
insulin, IGF-1
99
where is the Steroid receptor located
in the cytoplasm bound to heat shock proteins;
when steroid ligand binds, HSP dissociates and nuclear translocation signal is exposed and initiates transport into nucleus where it will bind with the hormone response element, initiating transcription etc.
100
how do steroid hormone receptors work
Inactive receptors in cytoplasm and nucleus
Bound to heat shock proteins (hsp)
Ligand binding causes dissociation of hsp and ability to bind to and activate DNA
101
