Pituitary/H/R/Onc Flashcards

1
Q

how does PRL cause hypo hypo

A

inhibiting hypothalamic gonadotropin-releasing hormone secretion

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2
Q

how to screen for macroPRL

A

polyethylene glycol precipitation

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3
Q

PRL stimuli

A

TRH
GHRH
Estradiol
Oxytocin
VIP
Serotonin

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4
Q

inhibitors of PRL

A

dopamine
Prolactin
○ Inhibits it’s own release
○ Stimulates dopamine - likely to inhibit itself

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5
Q

PRL levels

A

50-250 ng/mL :Drug induced

<40-60 ng/mL: Venipuncture stress and breast stimulation

25-100 ng/mL: secondary to a non-functioning mass that interrupts the dopamine neurons

100-250 ng/mL: microadenomas (prolactinomas </= 1 cm)

> 500 ng/mL: macroprolactinomas

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6
Q

usually first sign in hyperPRL

A

hypogonadism
(more than lactation)

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7
Q

first labs to do when PRL high to r/o other

A

HCG and TFT and GH

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8
Q

tx hyperPRL

A

dopamine agonist
- bromocryptine
- carbergoline

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9
Q

causes of hyperPRL

A
  • Prolactinoma
  • Macroprolactinemia: due to antibodies causing a large prolactin aggregate, which is not active so has no symptoms, but only increases bound prolactin
  • Pituitary stalk disruption
    ○ Non-functioning tumours, craniopharyngiomas, granulomatous infiltration, TBI
    ○ Decreased dopamine inhibition from hypothalamus
  • Stress - surgery, exercise, hypoglycemia, acute MI
  • Breast disease, nipple stimulation, disease or injury to the chest wall, spinal cord injury, burns, herpes zoster
    ○ Neurogenic reflex: PRL secretion stimulated by activation of afferent neural pathways
  • Hypothyroidism
    ○ Hyperplasia of lactotrophs and thyrotrophs, presumably due to TRH hypersecretion
  • Dopamine receptor blockers (metoclopramide, antipsychotics): stops dopamine from inhibiting prolactin release
  • Renal failure and liver failure
    ○ Impaired renal degradation of prolactin and altered central prolactin regulation
  • Estrogen: binds to estrogen receptor (response element) that controls the prolactin gene in the lactotrophs
  • Pregnancy/lactation: physiologic increases prolactin
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10
Q

meds causing hyperPRL

A

rispiridone
olanzapine

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11
Q

size of PRLoma

A

Macroprolactinoma: >/=1cm
Microprolactinoma: <1cm

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12
Q

syndromes w PRLoma

A

MEN1’
Familial hyperprolactinemia
Familial isolated pituitary adenoma

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13
Q

most common H w pit adenoma

A

PRLoma - 66%

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14
Q

indications to treat PRLoma

A

○ Galactorrhea
○ Amenorrhea/Hypogonadism (if bothersome, could observe if isolated symptom)
○ DESIRE Planning pregnancy
○ Visual field deficits
○ If medication-induced and the med cannot be stopped or substituted and symptomatic (indication for surgery)
○ If impact on bone health (low BMD) + hypogonadotropic hypogonadism
○ Pituitary macroadenoma (not appropriate for observation alone)

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15
Q

Adv/Disadv of dopamine agonists in PRLoma

A

Bromocriptine
§ Advantage: reduces adenoma size effectively
§ Disadvantage: nausea (++), not as effective at lowering prolactin levels as cabergoline, given daily

Cabergoline
§ Advantages: only administered once or twice a week, higher rates of success suppressing prolactin, better tolerated
§ Disadvantage: risk of valvular heart disease (seen at high doses used in Parkinson’s tx)

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16
Q

TSH B subunit - genes needed

A

POUF1
GATA2

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17
Q

stimulants of TSH secretion

A
  • TRH
  • Low T3
    ○ PTU
  • Low T4
    ○ Iodine Def
  • Leptin
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18
Q

inhibitors of TSH secretion

A
  • SRIF
  • T3 > T4
  • Glucocorticoids
  • Dopamine (acutely)
  • Fasting/Starvation
  • Antiepileptics
  • Certain cytokines
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19
Q

ACTH stim by?

A

CRH
AVP

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20
Q

ACTH prod cells

A

Corticotrophs

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21
Q

key genes for ACTH

A

TBX19
TPIT

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22
Q

what R does ACTH bind

A

MC1R -> hyperpigmentation
MC2R -> adrenal steroidogenesis

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23
Q

2 neurons ADH is made

A

magnocellular -> sends ADH to post pit
parvocellular -> sends ADH to ant pit -> enhances ACTH secretion

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24
Q

2 most imp gene GnRH devel

A

KAL1
PROK2

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25
hormones that are peptides
HT ○ TRH, CRH, GHRH, GnRH ○ AVP, Oxy ○ SRIF PIT ○ ACTH
26
hormones that are Glycoproteins
LH, FSh, TSH
27
hormones that are proteins
GH, PRL
28
nuclear receptor hormones
- cortisol - TH - E - Proges - testo - Aldo - vit D
29
Thyroid hormone receptor type and locaton
Nuclear R
30
Steroid hormone receptor type
Nuclear
31
TSH receptor type and location
G-protein coupled receptor = located in cell membrane
32
GPCR Gsa - list
TSH LH / HCG FSH CRH ACTH/MSH GHRH PTH
33
GPCR Gqa - list
GnRH TRH ADH Oxytocin
34
GPCR Qia
Somatostatin Dopamine
35
GOF mutations ○ Gas ○ LH receptor ○ TSH receptor ○ PTH-PTHrp receptor ○ Calcium sensing receptor
○ Gas § Mc-Cune Albright syndrome ○ LH receptor § Familial Male Precocious puberty ○ TSH receptor § Congenital hyperthyroidism ○ PTH-PTHrp receptor § Osteitis fibrosa cystic ○ Calcium sensing receptor § Familial hypercalciuric hypcalcemia
36
LOF mutations ○ TSH receptor ○ Calcium sensing receptor ○ Gas ○ Vasopressin receptor ○ LH/hCG receptor
○ TSH receptor § TSH resistance ○ Calcium sensing receptor § Familial hypocaluric hypercalcemia, Severe neonatal hyperparathyroidism ○ Gas § PHP (maternal inheritance) – AHO □ PTH , GHRH, TRH resistance § PHP (paternal inheritance) □ AHO ○ Vasopressin receptor § Nephrogenic diabetes insipidus ○ LH/hCG receptor § XY female, testicular unresponsiveness to LH
37
* Germline GPCR activating mutations
§ KISS1R – precocious puberty § CASR – autosomal dominant hypocalcemia § PROKR2 – precocious puberty § LHCGR (LH receptor) – pseudoprecocious puberty, testotoxicosis § FSHR – ovarian hyperstimulation § TSHR – hyperthyroidism, neonatal thyrotoxicosis § MC2R (ACTHR) – Cushing syndrome § PTH1R – metaphyseal chondrodysplasia § AVPR2 – Nephrogenic SIADH § GPR101 – X-linked acro-gigantism (overgrowth syndrome, excess GH from pituitary adenoma or hyperplasia)
38
PTH-R mutation
§ Activating: Jansen-type metaphyseal chondrodysplasia § Inactivating: Homozygous: Blomstrand’s chondrodysplasia
39
CaSR mutations
§ Inactivating 1. Familial benign hypocalciuric hypercalcemia (hetero) 2. Neonatal severe hyperparathyroidism (homo) § Activating (heterozygous) AD hypocalcemic hypercalciuria Bartter syndrome type V
40
MC2R mutation
Familial glucocorticoid deficiency type 1
41
V2 receptor type?
GPCR - Gqa
42
V2 mutation
Inactivating: X-linked Nephrogenic DI Activating:Nephrogenic SIADH
43
Cytokine Receptors - hormones?
PRL GH Leptin
44
Inactivating mutations in Cytokine R
GHR - GH insensitivity - Laron dwarfism - Partial GH insensitivity Leptin R - obesity + hypohypo
45
Tyrosine Kinase Receptors
Insulin IGF1 FGFR1 FGFR2 FGFR3
46
what is Ant Pit made from in development - what is that made from
Rathke's pouch from Oral ectoderm and neuroectoderm
47
what is post pit made from
ventral HT and 3rd ventricle
48
what part of the gland is the rathe pouch come from
Pars intermedia: remnant tissue (Rathke pouch)
49
What is GATA2 important for
TSH LH FSH
50
MRI findings that can be assoc w hypopit
* Absent posterior pituitary * Optic nerve hypoplasia * Ectopic posterior pituitary * Small anterior pituitary * Thin pituitary stalk * Pituitary stalk thickening * Absent corpus callosum * Absent septum pellucidum * Holoprosencephaly * Schizencephaly * Cerebellar hypoplasia * Chiari malformation * Empty sella * Hypothalamic hamartoma * Aplasia of the fornix
51
Cause of thickened stalk
Germinoma TB Langerhans Cell Hypophisitis Lymphocytic Hypophysitis Sarcoidosis - ectopic neurohypophysis - Rathke cleft cyst - Pituitary adenoma - Craniopahryngioma
52
H def w thickened stalk
w○ Central DI (91.3%) down ○ Growth hormone deficiency (GHD) (56.5%) down ○ Hyperprolactinemia (39%) up ○ Central hypothyroidism (34.8%) down ○ Adrenal insufficiency (9%) down ○ Precocious puberty (8.7%) up **For pituitary stalk thickening you have deficiencies except breast development! (think prolactin and precocious puberty)
53
when does ectopic PP happen?
when the posterior pituitary gland is incompletely descended anywhere along the path of the pituitary stalk.
54
if you can see the stalk, what is most likely H def?
When the stalk is visualized, the clinical presentation is more often isolated GH deficiency rather than multiple pituitary hormone deficiencies
55
functional adenoma - H?
- Prolactinoma (66%) - Growth-hormone producing (9-13%) - ACTH-producing (4-6%) - TSH-secreting (0.5-3%) - Gonadotroph-secreting (very rare)
56
pituitary is where?
sella
57
does non functioning adenoma cause H def?
could cause hyperPRL from compression
58
Risk of PRLoma in pregnancy
MicroPRLoma: <5% MacroPRLoma: 31%
59
PRL levels increasing during pregnancy normal?
10fold increase
60
Neonatal signs of hypopit
* Midline defects * Short * Cleft Lip/palate, craniofacial abnormalities * Central incisor * Micropenis (FSH, LH) * Cryptorchidism (FSH, LH) * Mutation – agenesis or CC, absent pit, etc) * Hypotension (ACTH) * Large posterior fontanel, large tongue, umbilical hernia (TSH) * Hypoglycemia (GH, ACTH) * Hyponatremia (ACTH (b/c increased AVP), TSH * Liver * Hyperbili (TSH) * Cholestatic jaundice * Giant cell hepatitis * Poor feeding * apnea * jitteriness * temp instability
61
Hypothalamic problems - signs of?
Hypothalamus often accompanied by: - Appetite defects (hypothalamic obesity) - Thermoregulation defects - Sleep defects
62
Signs of SOD
○ Wandering gaze ○ Pituitary deficiency – hypoglycemia ○ Midline defects ○ Optic nerve hypoplasia ○ Development – normal to severely delayed ○ 30% have complete triad
63
SOD H def
○ GH = most common ○ TSH ○ ACTH ○ GnRH = least common Ant Pit Def ○ DI = least common overall
64
Psychosocial dwarfism
- Triad ○ Short stature ○ Insatiable appetite ○ Pubertal delay / delated sexual maturation - Also ○ strange eating habits ○ infant feeding difficulties, sleep problems, delayed speech, malabsorption, abdominal protuberance - Generally reduced GH secretion No response to GH until psychosocial problems improve
65
Pituitary apoplexy - what is it
caused by bleeding into and/or hypoperfusion of a hypothalamic/pituitary lesion. Apoplexy can cause pituitary hormone deficiencies, although the presentation is often acute
66
H def from infection? most likely? when to resolve
somatotropin and gonadotropin deficiencies DI rare usually resolve w/in 6 m
67
causes of acquired hypopit
Most common: MASSES Other causes: - Head trauma - Infection -Infiltrative - Sarcoidosis - LCH ○ DI first - Inflammatory - Lymphocytic hypophysitis (autoimmune) - Infectious - Meningitis, encephalitis - Psychosocial Dwarfism
68
what can insulin tolerance test test?
GH axis ACTH - Cortisol axis
69
TKI in cancer therapy - endo outcome
Tyrosine kinase inhibitors can cause varying degrees of loss of growth potential due to disruption of growth hormone signal transduction.
70
Germinoma pathophys pres
- Stalk involvement - DI most common ○ Then growth ○ Then puberty (may be precocious) Good response to XRT
71
risk of DTC w RT
○ Risk of differentiated thyroid cancer (DTC) increases linearly until 10 Gy ○ Plateaus from 10-30 Gy ○ Decreases at doses >30 Gy
72
female cancer survivors - risk of POI - increased risk w?
8% risk of developing POI * Individuals at highest risk: - alkylating agents - abdominal radiotherapy - hematopoietic stem cell transplant
73
POI def'n for cancer survivor
- Absence of menses for >/= 4 mos AND elevated FSH levels in the menopause range x 2 OR - Delayed or arrested pubertal progression in girls >/= 13 yo
74
fertility preservation options in girls
○ Oocyte and embryo cryopreservation Prepubertal girls scarcity of evidence for ovarian tissue cryopreservation
75
what effects gonads in males in oncology tx?
**Chemotherapy impacts spermatogenesis **Radiotherapy impacts testosterone production
76
how to assess spermatogenesis in males?
Semen analysis = gold standard primary surveillance also Testicular volumes + FSH + inhibin B
77
how is ant pit formed
Invagination of Rathke’s Pouch (ectoderm)
78
what is pars intermedia
boundary between anterior & posterior – remnant of Rathke’s Pouch
79
what ant pit hormones do not bind to protein coupled receptors
what ant pit hormones DO NOT bind to Protein coupled receptor
80
what kind of hormones are TRH, CRH, GHRH, GnRH
peptides
81
what kind of hormones are the following hormones: ACTH: LH, FSH, TSH: GH, PRL:
ACTH: Peptide LH, FSH, TSH: Glycoproteins GH, PRL: Protein
82
in GPCR what does Gqα do
ACTH: Peptide LH, FSH, TSH: Glycoproteins GH, PRL: Protein
83
in GPCR what does Gsα do
stimulates AC, makes PKA Adenyl cyclase Protein kinase A
84
what hormones bind to Gsα
CRH ACTH TSH GHRH LH,FSH CaSR PTH
85
what hormones bind to Gqα
TRH GnRH GHS-R AVP (1b) Oxy
86
in GPCR what does Giα do
inhibits Adenyl cyclase
87
what stimulates GH
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
88
What inhibits GH secretion
Hormones: SRIF IGF-1 Hypothyroidism Hyperthyroidism Glucocorticoids Chronic admin Deficiency Nutrition: Glucose FFA Other: Depression Emotional deprivation β-adrenergy
89
what hormones share a common Alpha unit and have a specific beta unit
TSH LH FSH HCG CαSβ Common Alpha Specific Beta Rock the Casbah
90
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
91
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
92
pathologic cause of high PRL
Prolactinoma (> 1000ug/dl) Stalk Compression/dissection Hypothyroidism Surgery Seizure Head Trauma Renal Failure Hypothalamic mass Prolactin receptor mutation
93
physiologic causes of hyperPRL
Pregnancy Lactation Stress Coitus Nipple stimulation Sleep Exercise
94
what drugs can cause high prolactin
Dopamine antagonists (Parkinson meds) Antipsychotics: Risperidone Estrogen Ranitidine Anti epileptics: Phenytoin Opiates Anti depression: SSRIs, TCAs
95
What syndrome to think of w PRLoma
MEN1
96
most common presentation of PRLoma
hypogonadism
97
w/u for hyperPRL
TFTs Macroprolactin (less bioactive)
98
most common tumours affecting pituitary
1) craniopharyngioma 2) pituitary adenoma germinoma
99
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
100
Pituitary adenoma - most common pit abn
PRL ACTH
101
germinoma - most common assoc
DI because of stalk DI most common, followed by growth, puberty (may be precocious)
102
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
103
infiltrative causes of hypo pit
Sarcoidosis LCH
104
inflammatory causes hypopit
Lymphocytic hypophysitis (autoimmune)
105
What will unmask central AI
T4 GH
106
what will unmask Central DI
cortisol T4
107
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
108
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
109
adv/dis for carbergoline s/e
● 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)
110
adv/dis for bromocryptine s/e
● 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)
111
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
112
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)
113
what is most common deficiency with holoprosencephaly
DI - 70% of individuals with holoprosencephaly have DI Anterior pituitary deficiencies are less common
114
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.
115
liver finding in hypopit
giant cell hepatitis
116
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.
117
antenatal u/s signs of hypopit
Cleft Lip/palate Abnormal midline brain malformation - Absence/dysgenesis of corpus callosum, absence/dysgenesis of septum pellucidum, holoprosencephaly Craniofacial abnormalities Umbilical hernia (TSH) Bradycardia (TSH) Micropenis (GH, LH/FSH) Cryptorchidism (LH/FSH) - but won’t see this on US ***not IUGR - usually normal BW, then have poor weight gain