Pituitary/H/R/Onc Flashcards
how does PRL cause hypo hypo
inhibiting hypothalamic gonadotropin-releasing hormone secretion
how to screen for macroPRL
polyethylene glycol precipitation
PRL stimuli
TRH
GHRH
Estradiol
Oxytocin
VIP
Serotonin
inhibitors of PRL
dopamine
Prolactin
○ Inhibits it’s own release
○ Stimulates dopamine - likely to inhibit itself
PRL levels
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
usually first sign in hyperPRL
hypogonadism
(more than lactation)
first labs to do when PRL high to r/o other
HCG and TFT and GH
tx hyperPRL
dopamine agonist
- bromocryptine
- carbergoline
causes of hyperPRL
- 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
meds causing hyperPRL
rispiridone
olanzapine
size of PRLoma
Macroprolactinoma: >/=1cm
Microprolactinoma: <1cm
syndromes w PRLoma
MEN1’
Familial hyperprolactinemia
Familial isolated pituitary adenoma
most common H w pit adenoma
PRLoma - 66%
indications to treat PRLoma
○ 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)
Adv/Disadv of dopamine agonists in PRLoma
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)
TSH B subunit - genes needed
POUF1
GATA2
stimulants of TSH secretion
- TRH
- Low T3
○ PTU - Low T4
○ Iodine Def - Leptin
inhibitors of TSH secretion
- SRIF
- T3 > T4
- Glucocorticoids
- Dopamine (acutely)
- Fasting/Starvation
- Antiepileptics
- Certain cytokines
ACTH stim by?
CRH
AVP
ACTH prod cells
Corticotrophs
key genes for ACTH
TBX19
TPIT
what R does ACTH bind
MC1R -> hyperpigmentation
MC2R -> adrenal steroidogenesis
2 neurons ADH is made
magnocellular -> sends ADH to post pit
parvocellular -> sends ADH to ant pit -> enhances ACTH secretion
2 most imp gene GnRH devel
KAL1
PROK2
hormones that are peptides
HT
○ TRH, CRH, GHRH, GnRH
○ AVP, Oxy
○ SRIF
PIT
○ ACTH
hormones that are Glycoproteins
LH, FSh, TSH
hormones that are proteins
GH, PRL
nuclear receptor hormones
- cortisol
- TH
- E
- Proges
- testo
- Aldo
- vit D
Thyroid hormone receptor type and locaton
Nuclear R
Steroid hormone receptor type
Nuclear
TSH receptor type and location
G-protein coupled receptor = located in cell membrane
GPCR Gsa - list
TSH
LH / HCG
FSH
CRH
ACTH/MSH
GHRH
PTH
GPCR Gqa - list
GnRH
TRH
ADH
Oxytocin
GPCR Qia
Somatostatin
Dopamine
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
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
- 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)
PTH-R mutation
§ Activating: Jansen-type metaphyseal chondrodysplasia
§ Inactivating:
Homozygous: Blomstrand’s chondrodysplasia
CaSR mutations
§ Inactivating
1. Familial benign hypocalciuric hypercalcemia (hetero)
2. Neonatal severe hyperparathyroidism (homo)
§ Activating (heterozygous)
AD hypocalcemic hypercalciuria
Bartter syndrome type V
MC2R mutation
Familial glucocorticoid deficiency type 1
V2 receptor type?
GPCR - Gqa
V2 mutation
Inactivating: X-linked Nephrogenic DI
Activating:Nephrogenic SIADH
Cytokine Receptors - hormones?
PRL
GH
Leptin
Inactivating mutations in Cytokine R
GHR - GH insensitivity
- Laron dwarfism
- Partial GH insensitivity
Leptin R
- obesity + hypohypo
Tyrosine Kinase Receptors
Insulin
IGF1
FGFR1
FGFR2
FGFR3
what is Ant Pit made from in development
- what is that made from
Rathke’s pouch from Oral ectoderm and neuroectoderm
what is post pit made from
ventral HT and 3rd ventricle
what part of the gland is the rathe pouch come from
Pars intermedia: remnant tissue (Rathke pouch)
What is GATA2 important for
TSH
LH
FSH
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
Cause of thickened stalk
Germinoma
TB
Langerhans Cell Hypophisitis
Lymphocytic Hypophysitis
Sarcoidosis
- ectopic neurohypophysis
- Rathke cleft cyst
- Pituitary adenoma
- Craniopahryngioma
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)
when does ectopic PP happen?
when the posterior pituitary gland is incompletely descended anywhere along the path of the pituitary stalk.
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
functional adenoma - H?
- Prolactinoma (66%)
- Growth-hormone producing (9-13%)
- ACTH-producing (4-6%)
- TSH-secreting (0.5-3%)
- Gonadotroph-secreting (very rare)
pituitary is where?
sella
does non functioning adenoma cause H def?
could cause hyperPRL from compression
Risk of PRLoma in pregnancy
MicroPRLoma: <5%
MacroPRLoma: 31%
PRL levels increasing during pregnancy normal?
10fold increase
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
Hypothalamic problems - signs of?
Hypothalamus often accompanied by:
- Appetite defects (hypothalamic obesity)
- Thermoregulation defects
- Sleep defects
Signs of SOD
○ Wandering gaze
○ Pituitary deficiency – hypoglycemia
○ Midline defects
○ Optic nerve hypoplasia
○ Development – normal to severely delayed
○ 30% have complete triad
SOD H def
○ GH = most common
○ TSH
○ ACTH
○ GnRH = least common Ant Pit Def
○ DI = least common overall
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
- Also
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
H def from infection? most likely?
when to resolve
somatotropin and gonadotropin deficiencies
DI rare
usually resolve w/in 6 m
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
what can insulin tolerance test test?
GH axis
ACTH - Cortisol axis
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.
Germinoma
pathophys
pres
- Stalk involvement
- DI most common
○ Then growth
○ Then puberty (may be precocious)
Good response to XRT
- DI most common
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
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
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
fertility preservation options in girls
○ Oocyte and embryo cryopreservation
Prepubertal girls scarcity of evidence for ovarian tissue cryopreservation
what effects gonads in males in oncology tx?
**Chemotherapy impacts spermatogenesis
**Radiotherapy impacts testosterone production
how to assess spermatogenesis in males?
Semen analysis = gold standard primary surveillance
also
Testicular volumes + FSH + inhibin B
how is ant pit formed
Invagination of Rathke’s Pouch (ectoderm)
what is pars intermedia
boundary between anterior & posterior – remnant of Rathke’s Pouch
what ant pit hormones do not bind to protein coupled receptors
what ant pit hormones DO NOT bind to Protein coupled receptor
what kind of hormones are TRH, CRH, GHRH, GnRH
peptides
what kind of hormones are the following hormones:
ACTH:
LH, FSH, TSH:
GH, PRL:
ACTH: Peptide
LH, FSH, TSH: Glycoproteins
GH, PRL: Protein
in GPCR what does Gqα do
ACTH: Peptide
LH, FSH, TSH: Glycoproteins
GH, PRL: Protein
in GPCR what does Gsα do
stimulates AC, makes PKA
Adenyl cyclase
Protein kinase A
what hormones bind to Gsα
CRH
ACTH
TSH
GHRH
LH,FSH
CaSR
PTH
what hormones bind to Gqα
TRH
GnRH
GHS-R
AVP (1b)
Oxy
in GPCR what does Giα do
inhibits Adenyl cyclase
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
What inhibits GH secretion
Hormones:
SRIF
IGF-1
Hypothyroidism
Hyperthyroidism
Glucocorticoids
Chronic admin
Deficiency
Nutrition:
Glucose
FFA
Other:
Depression
Emotional deprivation
β-adrenergy
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
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
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
pathologic cause of high PRL
Prolactinoma (> 1000ug/dl)
Stalk Compression/dissection
Hypothyroidism
Surgery
Seizure
Head Trauma
Renal Failure
Hypothalamic mass
Prolactin receptor mutation
physiologic causes of hyperPRL
Pregnancy
Lactation
Stress
Coitus
Nipple stimulation
Sleep
Exercise
what drugs can cause high prolactin
Dopamine antagonists (Parkinson meds)
Antipsychotics: Risperidone
Estrogen
Ranitidine
Anti epileptics: Phenytoin
Opiates
Anti depression: SSRIs, TCAs
What syndrome to think of w PRLoma
MEN1
most common presentation of PRLoma
hypogonadism
w/u for hyperPRL
TFTs
Macroprolactin (less bioactive)
most common tumours affecting pituitary
1) craniopharyngioma
2) pituitary adenoma
germinoma
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
Pituitary adenoma - most common pit abn
PRL
ACTH
germinoma - most common assoc
DI because of stalk
DI most common, followed by growth, puberty (may be precocious)
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
infiltrative causes of hypo pit
Sarcoidosis
LCH
inflammatory causes hypopit
Lymphocytic hypophysitis (autoimmune)
What will unmask central AI
T4
GH
what will unmask Central DI
cortisol
T4
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
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
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)
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)
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
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)
what is most common deficiency with holoprosencephaly
DI - 70% of individuals with holoprosencephaly have DI
Anterior pituitary deficiencies are less common
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.
liver finding in hypopit
giant cell hepatitis
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.
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
