Pituitary/hypothalamus

Front 1

Where did the Pituitary gland come from?

i.e Embryology

Back 1

Ant Pit= Invagination of the Rathke's Pouch (Ectoderm)

Post Pi= Invagination of the Vental HT + 3rd Ventricel (Ectoderm)

Stalk= Median eminence of the HT

Pars Intermedia= Remnant of the Rathke's pouch

Front 2

Types of Neurons secreting Pituitary Hormones?

Back 2

Hypophysetropic Neurons: Cell bodies in the HT (PVN + ARC) secrete hormones that is carried by the Hypophyseal Portal circulation.

-TRH, CRH, GHRH, GHIH (somatostatin), GnRH, DA.

Magnocellular Neurons (PVN + SON): cell bodies in HT and hormones are carried along the axons to be secreted in the Pituitary.

-AVP, OXY

Front 3

All Hypothalamic hormones are ___________

except ____________

Back 3

All Hypothalamic hormones are peptides except DA which is an Amine.

Front 4

All Hypothalamic hormones work through

_____________ receptors

Back 4

GPCRs

Front 5

Describe hormone interaction between

HT--> Pituitary

Back 5

GHRH : ++ GH

TRH: ++ TSH

DA: ++ PRL

GNRH: ++ LH/FSH

CRH: ++ACTH

GHIH: -- GH, TSH

DA: -- PRL, TSH, LH/FSH

OXY: ++ PRL

AVP: ++ ACTH

Front 6

When is the Ant Pituitary recognizable during pregnancy? And when does it mature?

Back 6

5 WGA

20 WGA

Front 7

What is the earliest cells to develop in the Pituitary?

Back 7

Corticotrophs: 5 WGA then

Somatotrophs: 6 WGA then

Gonadotrophes + Throtrophes: 12 WGA then

Lacotrophes are the last at 24 WGA.

Front 8

What are some of the important transcription factors involved in Pituitary migration and commitment?

Back 8

Remember if it has "2" it involves the eyes and also has an AD inheritance.

HESX1: AR, SOD, Ant/Pos Hormone --.

PITX2: AD, Eyes, Umbilical defect, Pit Defect = Rieger's Syndrome

LHX3: AR, Ant Pit, SNHL

LHX4; AD, Ant Pit, Cerebellar

OTX2: AD, no eyes, Hypopit.

SOX3: XLR, Pit Defects, DD

SOX2: AD, no eyes, Hypopit.

Front 9

What would be a general rule for Transcription factors defects in the Pituitary?

Back 9

• Variable
  
• Can evolve overtime
  

Front 10

Pituitary Transcription factor defects

PROP1

Back 10

• AR
  
• Hypogonadism + GHD
  
• Can develop panhypo overtime.
  

Front 11

Pituitary Transcription factor defects

POU1F1

Back 11

• AR/AD
  
• AKA= PIT1
  
• GH + PRL + TSH
  

Front 12

Pituitary Transcription factor defects

TIPT

Back 12

• AR
  
• ACTH deficeincy
  

Front 13

Pituitary Transcription factor defects

HESX1

Back 13

• SOD
  
• Variable Ant + Post deficiencies
  

Front 14

Pituitary Transcription factor defects

LHX3

LHX4

Back 14

LHX3

• AR
  
• Vertebral
  

LHX4

• AD
  
• Hind brain defects: Cerebellar/Chiari Malformation.
  

Front 15

Anterior Pituitary hormone signalling?

Back 15

They act on cell surface/Trans-membrane receptors:

• GPCRs: LH/FSH/TSH/HCG/ACTH
  
• Cytokine receptors: GH/PRL

Front 16

Anterior Pituitary hormone structure ?

Back 16

Structure:

• Common Alpha subunit, variable Beta subunit.
  
• LH/FSH/TSH/HCG: glycoprotein.
  
• ACTH: Peptide
  
• GH/PRL: Proteins.
  

Front 17

Anterior Pituitary hormone synthesis and secretion?

Back 17

• Stored in vesicles until released
  
• Drains in the Pituitary veins --> Cavernous sinuses --> Petrosal veins --> Jugular vein.
  

Front 18

Growth Hormone structure and why it is important to know?

Back 18

22kd: 75% of circulating

20kd: ~10 of ciruculating

synthetic GH: 22kd so if doping 22kd:20kd ratio would be increased.

Front 19

HPGH axis?

Back 19

GHRH --> ++GH -->++IGF-1

GHIH --> --GH

IGF-1 --> ++GHIH, --GH

Grehlin --> ++GH, ++GHRH

Front 20

What increases GH secretion?

Back 20

• GHRH
  
• Hypoglycemia
  
• Arginine
  
• Clonidine
  
• L-Dopa
  
• Grehlin
  
• Galanin
  
• Steroid
  
• Stress
  
• Excercise
  

Front 21

What decreased GH secretion?

Back 21

• GHIH
  
• IGF-1
  
• Glucose
  
• FFA
  
• B-Adrenergy
  
• Depression/Deprivation
  
• Chronic Steroid use.
  

Front 22

GH secretion patterns?

Back 22

• GH secretion is pulsatile
  
• Diurnal pattern with 2/3 overnight.
  
• Triggered by slow wave sleep
  
• Pulsatile secretion maximally stimulates the receptors vs tonic secretion.
  
• Pulsatile secretion stimulates lipolysis while tonic secretion doesn't.
  
• RhGH acheives a single peak and suppresses endogenous GH secretion.
  

Front 23

What transcription factors are important for TSH synthesis?

Back 23

POU1F1 + GATA2 important for beta-subunit of TSH.

Front 24

GH secretion patterns?

Back 24

• Circadian Rhythm 11p - 5 a
  
• Ultradian rhythm ~ low amplitude which is not clinically important.
  

Front 25

What increases TSH secretion?

Back 25

• TRH
  
• Leptin
  

Front 26

Why is relevant that Leptin stimulates TSH?

Back 26

Because kids with Leptin deficiency can have central hypothyroidism.

Front 27

What decreased TSH secretion?

Back 27

• GHIH
  
• Fasting and Starvation (They decrease TRH)
  
• T3
• Dopamine (Acute effect)
• Glucocorticoids
• Some cytokines.

Front 28

Random Question: what kinds of Deiodinases are present in the :

• Hypothalamus
  
• Pituitary
  

Back 28

Hypothalamus: Type 3

Pituitary: Type 2, 3

Front 29

How is ACTH made ?

Back 29

POMC is converted by PC1 to

• ACTH
  
• gamma-MSH
  
• Beta-Lipotropin
  

Front 30

What transcription factor is important for ACTH synthesis?

Back 30

TPIT is essential for POMC synthesis

Front 31

What is POMC converted into ?

Back 31

PO

Front 32

What are the sites of the different PC enzymes?

Back 32

PC1: HT + Pituitary

PC2: CNS except Pituitary, Islets, Skin

Front 33

What do you know about the Melanocortin receptors?

Back 33

MCR-1: on melanocytes i.e causes skin pigmentation. Stimulated by MSH mainly but also ACTH (causes hyper-pigmentation in Addison's), B/G Lipotropin.

MCR-2: on the adrenal cortex and causes GC secretion, adrenal steroid and to a lesser extent MC.

MCR-3,4: on the Satiety centre in the HT. Stimulated mainly by Alpha-MSH. Also present in the Immune system.

Front 34

True or False:

POMC is expressed in the placenta

Back 34

True

Front 35

Obese + Red hair + Adrenal Insufficiency?

Back 35

POMC mutation

Homozygous or compound Heterozygous.

Front 36

Obesity + Adrenal Insufficiency + Hypogonadotropic Hypogonadism + Post-Prandial Hypoglycemia?

Back 36

PC1 mutation= PCKS1 mutation: AR but can be AD as well.

Reason for Post-Prandial Hypoglycemia is that you have lots Pro-Insulin that is not converted into insulin.

Also may have DI and Diarrhea (Intestinal expression)

Front 37

What increases ACTH secretion?

Back 37

• CRH
  
• AVP
  
• Hypoglycemia
  
• VIP, Cytokines, Stress, depression, Ghrelin.
  

Front 38

What decreases ACTH secretion?

Back 38

• GC
  
• ANP
  
• Opiates
  

Front 39

ACTH secretion patterns?

Back 39

Circadian rhythm: peak at 4-7 AM

Ultradian rthym: ~40 bursts per 24 hours.

Cortisol pulses follow after 5-10 mins

Front 40

Describe the ACTH action on the Adrenal cortex?

Back 40

ACTH acts on MC2R which is a GPCR which activates AC which activates and regulates:

1. Synthesis of cortisol > Androgens > MC
   
2. Mitochondrial transport of Cholesterol
   
3. Conversion of Cholesterol to Pregnenolone.
   

Grossly it is trophic to the Adrenal cortex.

Front 41

Why is puberty and smell sensation related?

Back 41

GNRH neuron migrate from the Olfactory placode to the HT.

Front 42

What transcription factors are important for GNRH neuron migration?

Back 42

• KAL1
  
• FGFR1
  
• PROK2/PROK2R
  
• NELF
  

Front 43

What transcription factors are important for GNRH secretion?

Back 43

Increases secretion:

• Kisspeptin
  
• Kisspeptin R = GPR54
  
• Leptin (++ pulses i.e required for puberty)
  

Decreases secretion:

• MKRN3 (mutations cause CPP)
  

Front 44

Describe Gonadotropin secretion in fetal/early infancy?

Back 44

Gonadotrpin mature by 12 WGA and start secreting LH/FSH

Peak at 20-24 WGA

Drop at late pregnancy

Birth: Peak to pubertal levels as feto-placental hormone levels drop

Front 45

True or false :

LH/FSH is higher in F > M fetuses

Back 45

True

Front 46

Mini-Puberty?

Back 46

LH rise from ~5-14 days- 3 months

FSH rise from few weeks to 1 yr (M) - 2 yr (F).

Front 47

Main Gonadotropin during preganacy?

Back 47

HCG~predominant

LH/FSH are not required for gonadal development and differentiation.

However some studies shows that they some what affect number of germs cells/Oocytes as well as Leydig cell number.

Also LH is important for penile length

Front 48

Gonadotropins Life cycle?

Back 48

Front 49

LH/FSH secretion patterns?

Back 49

• GNRH amplitude and frequency determine LH/FSH secretion.
  
• Optimal pulses~ q 1-2 hrs
  
• LH/FSH pulses can be less or more frequent.
  
• Continuous GNRH suppresses LH/FSH secretion.
  
• LH pulsatility begins overnight in puberty and then it becomes day and night in Adulthood.

Front 50

What increases Gonadotropin secretion?

Back 50

• GNRH
  
• Estrogen ~mid-cycle (LH)
  
• Activin (FSH)
  
• Leptin (Permissive for GNRH)
  

Front 51

What Decreases Gonadotropin secretion?

Back 51

• Testosterone
  
• Progesterone
  
• Estrogen~other than mid-cycle.
  
• Inhibin A/B (FSH)
  
• PRL
  
• Opiate/Stress/GABA (Inhibits GNRH)
  

Front 52

Actions of LH & FSH?

Back 52

Men:

• LH : Leydig cell Testo production.
  
• FSH: Fertoli Cell ; Spermatogenesis/Testicular growth.
  
• Both work in synergy for Spermatogenesis.
  

Female:

• LH: Ovulation, Progesterone by Corpus Luteal cells, Androgens by Theca cells.
  
• FSH: Follicle maturation, Estradiol production.
  
• Both work in synergy for Estradiol production.
  

Front 53

Prolactin Structure?

Back 53

Looks like GH ~ 16 % shared residues

Looks like HPL ~ 13 % shared residues

Circulates in the following forms:

• Small monomeric form: 23 KD~ most bioactive.
• moderate size dimeric form.
• Big size Polymeric form.

Front 54

What is Macroprolactinemia?

Back 54

• Predominant dimeric/polymeric forms circulating.
  
• Benign because higher MW forms are less bioactive.
• Can measure relative concentrations of Big: Small forms to establish a diagnosis.
  

Front 55

What increases PRL secretion?

Back 55

• TRH
  
• Oxytocin
  
• Stress
  
• Sleep
• Estrogen
  
• Others (can't memorize now)
  

Front 56

What decreases PRL secretion?

Back 56

• DA
  
• GHIH
  
• Calcitonin
  

Front 57

PRL secretion pattern?

Back 57

• Increases at night i.e during sleep.
  
• Lowest between 10 AM - 12 PM.
  
• High during fetal/Pregnancy/early infancy then start to start to decline in the first few months of life and then decreases gradually by age.
  

Front 58

Prolactin Signalling?

Back 58

• Cytokine receptor --> JAK/STAT signalling.
  
• Receptor can dimerize independant of ligand.
  
• Receptor is in Breast, Pituitary, Liver and others.

Front 59

Hyperprolactinemia causes?

Back 59

Physiologic:

Pregnancy: (~200 ug/l)

Lactation (< 200 ug/ but declines even with continued lactation)

Sex (< 50)

Stress/exercise (< 50)

Sleep (< 50)

Pathological:

Prolactinoma (~1000s but any level)

Stalk Compression (<200)

Hypothyroid (<200)

Surgery (<200)

Seizures (<200)
Head Trauma (<200)
Renal Failure (<50)

Drugs:

DA antagonists~ antipsychotics. (<200)

• Respiridone is the most common medicine to cause HyperPRL. Olanzapine doesn't affects PRL.
  

Others (<50)

Front 60

Evaluation of Hyperprolactinemia?

Back 60

1. Rule out Macroprolactinemia????? if no Sx.
   
2. Rule out severe Hypothyroidism.
   
3. MRI.
   
4. > 200 ug/L = Prolactinoma (Lactrophs tumor).
   
5. Lacto-somatotroph tumors secrete both GH(Acromegaly) + PRL (Prolactinoma).
   
6. Don't forget about MEN1.

Front 61

Incidence of Prolactinoma?

Back 61

• 50-75% of Pituitary adenomas
  
• Present mainly in teens
  

Front 62

Most common presentation of Prolactinoma in children?

Back 62

Hypogonadism! ~ oligo/Amenorrhea/Pubertal delay or arrest.

+/- galactorrhea.

Front 63

Lines of treatment of prolactinoma?

Back 63

Medical~first line

DA agonist

• Bromocriptine~only one to be FDA approved in children.
  
• Cabergoline~ better tolerated.
  

Front 64

When is surgery indicated in prolactinoma?

Back 64

1. Failed medical treatment.
   
2. Intolerable side effects ~esp Bromocriptine.
   
3. Big tumor size that didn't shrink with medical therapy.
   

Front 65

Vasopressin structure, synthesis , storage and release?

Back 65

=Nonapeptide~ Oligopeptide

Precursor hormone = AVP + Neurophysin II + Copeptin.

Precursor hormone is stored in vesicles and when the stimulus arrives ~action potential --> Ca influx --> vesicles move to the synaptic membrane and release AVP, Neurophysin, Copeptin in 1:1:1 ratio.

The posterior Pituitary contains AVP stores enough for 5-10 days.

Front 66

What is Neurophysin II?

Back 66

1. It is a carrier protein
2. Mutations in Neurophysin II causes :
   

• Abnormal prehormone that leads to damage of the neurones --> central DI.
  
• Abnormal transport of AVP.

Front 67

Describe the main system that regulates the AVP release?

Back 67

1. Barorecptors in vessels/Atria
2. Osmostat in HT.
   

AVP release is more sensitive to Osmolality > Pressure/Volume i.e 1 % change in Osm vs 10-15 % change in Pressure/Volume is needed to stimulate AVP release.

Front 68

Types of Baroreceptors involved in AVP release?

Back 68

High pressure: Carotid sinus, Aortic arch.

Low pressure: i.e Volume receptors : Atria, Pulmonary veins.

Front 69

What other factors other than Osm/Pressure/Volume regulate the release of AVP?

Back 69

Modest effect:

• Glucocorticoid (Inhibit)
  
• Nausea/Vomiting/Pain (stimulate)
  

Front 70

AVP signalling?

Back 70

GPCRs

• V1 (V1a) = Vascular smooth muscles , 12q14
  
• V2=Kidney, Xq28
  
• V3 (V1b) = Pituitary, 1q32
  

Front 71

How is DDAVP different than Vasopression?

Back 71

• DDAVP has 2 different amino acid so that will only act on V2 receptors (i.e kidney only)
• Vasopressin will act on both V1 & V2 (i.e Vascular and Kidney)
  

Front 72

AVP action in the kidney?

Back 72

AVP will bind with V2 at the CT surface --> ++ CAMP --> ++ Aquaporin 2 channels at the Collecting duct --> ++ H2O reabsorbtion.

Also chronic AVP secretion --> ++ AQP2 & AQP3 synthesis

Front 73

What is the Triple response?

Back 73

1. DI (edema)
   
2. SIADH (necrosis)
   
3. DI (cell death)
   

*Can have an Isolated transient SIADH.

Front 74

Congenital causes of Central DI?

Back 74

• SOD
  
• Holoprosencehaly
  
• CNS Midline defects
  
• Familial AVP mutations
  

Front 75

What are the Familial AVP mutations?

Back 75

AR-AVP gene mutation.

• Presents in infancy
  

AD-Neurophysin II mutation (see before)

• slow so present in early-mid childhood
  

AR-DIDMOAD= Wolfram Syndrome

• Presents in 2nd decade.

Front 76

What are the acquired causes of Central DI?

Back 76

Trauma

Hypoxia/Ischemia

Tumors~ Germinoma/Cranio

Infection

Idiopathic

Drugs

Pregnancy (++ AVP by placenta)

Front 77

What do you need to keep an eye on in someone with idiopathic central DI?

Back 77

Germinoma~ can evolve overtime and needs to be monitors with q 6 mon - 1 yr MRIs.

Front 78

What are the congenital causes of nephrogenic DI?

Back 78

• AVP-R2 mutations (X-linked)
  
• AQP2 mutation (AR/AD)
  
• Bardet-Bidel: AVPR2 on defective cilia.

Front 79

What are the Acquired causes of nephrogenic DI?

Back 79

Drugs~ Lithium

Others

Front 80

Few things to know about Oxytocin

Back 80

++ Alveolar production

++ milk release (++ myoepithelial duct contraction)

Suckling stimulates OXY and keeps rising vs PRL that is stimulated and then goes down.

Front 81

Causes of Congenital Hypopituitarism?

Back 81

If : HypoPIT + Other CNS defects

• HESX1, SOX2 (see before)
  

If : HypoPIT + no other defects (only multiple hormone deficiency)

• PROP1, POU1F1
  

If : Isolated Hormone Deficiency

• GH: GH1, GHR
  
• ACTH: TPIT, PC1, POMC
  
• AVP: AVP, Neurophysin II
  
• LH/FSH: KAL1, FGFR1, PROK2/PROK2R, NELF.
  

Front 82

Differential Diagnosis of Sellar masses?

Back 82

1. Craniopharyngioma (MCC~90%)
2. Pituitary Adenomas (2nd MCC)~Prolactinoma then Cushing's disease.
3. Germinoma
4. Rathke's cleft cyst (benigh, potential for mass effect)
5. Optic Glioma.

Front 83

How can you differentiate prolactinoma from cushing's disease by Age?

Back 83

• Cushing's disease: mid childhood- adolescence.
  
• Prolactinoma: adolescence.
  

Front 84

Where does a germinoma grow?

Back 84

Hypothalamus, Stalk, Post Pituitary, Pineal gland.

Front 85

How does a germinoma present?

Back 85

DI (MC), poor growth, early/late puberty

Front 86

How would you treat a germinoma?

Back 86

RT +/- CT (highly radiosensitive --> high cure rates)

Front 87

Craniopharygioma pathology?

Back 87

Benign

2 types:

Adamantonamtous:

• Solid + cystic
  
• MC in Children
  
• B-Catenin mutations
  

Papillary

• Solid only
  
• BRAF mutations
  

Front 88

Craniopharyngioma peak age of onset?

Back 88

Bimodal

• Childhood (5-14)
  
• Older Adults (50's-60's)
  

Front 89

Craniopharyngioma presentation?

Back 89

HA, Visual (Think Abby)

Growth delay, Pubertal delay

Ant Pit Deficiencies

Post Pit Deficiencies (DI)

Front 90

Hypopituitarism following cranial irradiation?

Back 90

• <10 Gy: low risk
  
• >50 Gy: high risk
  
• Need to be followed for years as they can develop gradually.
  

Front 91

What are the acquired causes of Hypopituitarism?

Back 91

Injury (Head Trauma)

Infiltration

• LCH (DI MC presentation)
  
• Sarcoidosis
  

Infection: Meningitis, encephalitis.

Immune : Lymphocytic hypophysitis

Front 92

Psychosocial Dwarfism Classic Triad?

Back 92

1. Short Stature
   
2. Voracious Appetite
   
3. Delayed sexual maturation
   

GH is reduced but TTT with GH doesn't help.

TTT=place in a better environment

Front 93

GH axis and nutrition?

Back 93

Under nutrition:

• GH resistance (increased), --IGF-1.
  

Obesity:

• GH --, N/Low IGF-1, --IGFBP-1.
  

Front 94

HPA axis and nutrition?

Back 94

Under nutrition:

• ++ CRH, ACTH, Cortisol.
  

Obesity:

• ++ UFC, ++ 11-BHSD --> ++ tissue cortisol.
  

Front 95

HPG axis and nutrition?

Back 95

Under nutrition:

• -- LH/FSH, sex hormones
  

Obesity:

• F (PCOS), M (Hypogonadism)
  

Front 96

Pituitary Cross Talk?

Back 96

TH ++ Cortisol metabolism.

Cortisol --- AVP, +++ Free H2O clearance

TH +++ Free H2O clearance

Increases in LT4 & GC may Increase DDAVP dose.

HypoT --- GH responsivness

Testo (Directly) & Estrogen (indirectly by --IGF-1) ++++ GH

Cortisol + GH are counter regulatory hormones.