The Posterior Pituitary Lobe: Neuroendocrine, Clinical and Diagnostic Implications

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The Posterior Pituitary Lobe Neuroendocrine,
Clinical and Diagnostic Implications

• Gábor L. Kovács
• professor of laboratory medicine,
• University of Pécs, Hungary

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Pécs, a city of Mediterranean atmosphere

• The predecessor of Pécs in the Roman age,
  Sopianae was a provincial seat.
• The early Christian cemeteries of the city (4th
  century BC), are the most significant early
  Christian necropolis to be found outside of
  Italy.
• The bishopric of Pécs was founded in 1009.
• The university (the first one in Hungary) was
  founded in 1376.

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OVERVIEW

• Posterior pituitary
• Oxytocin
• Classical roles milk ejection, uterus
  contraction
• Effects on attachment
• Vasopressin
• Free water excretion, hyponatremia
• DI, SIADH, CSWS
• CNS effects learning, memory

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PITUITARY DEVELOPMENT
Hypothalamus
Posterior pituitary release of hormones
separated from production!!
Infundibular stem
Pars tuberalis
Pars nervosa
Pars distalis
ADENOHYPOPHYSIS
NEUROHYPOPHYSIS
Infundibular stem
Pars tuberalis
Pars intermedia
Pars nervosa
Pars distalis
Rathkes pouch lumen
Cysts
Pars intermedia
Cysts in pars intermedia remnants of Rathkes
pouch lumen?
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Processing throughout the secretory pathway
Signal sequence cleavage (ER)
Endoproteolytic cleavage (TGN or secretory
vesicle)
Carboxypeptidase (secretory vesicle)
Peptidyl-glycine-a-amidation (vesicle)
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Oxytocin

• Specific G protein- coupled receptors
• ? Frequency and force of uterine smooth muscle
  contraction during parturition
• ? Contraction of mammary myoepithelial cells
  and milk ejection
• Half-life 5 to 12 minutes

OT receptor binding ß phospholipase C ß IP3,
Ca2 ß contraction of uterine smooth muscle and
mammary myoepithelial cells



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Oxytocin secretion

• By hypothalamic oxytocinergic neurons
• In response to neural stimulation
• Parturition (distention of the cervix and
  vagina)
• Suckling
• Stimulated by plasma hypertonicity, hemorrhage

Other stimulatory factors Inhibitory factors
estrogen opioid peptides angiotensin II
severe pain VIP, cholecystokinin ?
temperature norepinephrine, nausea,
satiety psychological stress
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THE SUCKLING REFLEX
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3
Hypothalamic SO PV neuron activation
Sensory response
Hypothalamus
BREAST

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Oxytocin release
1
Stimulus
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Myoepithelial-cell contraction
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Vascular transfer
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NEW CONNECTIONS DICOVERED
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AXONAL ARM
OXYTOCIN THEN TRAVELS DOWN AXONAL TUBULES
TRANSPORT TUBULES
4 4
AXONAL FOOT
STORED at AXONAL FOOT in PACKETS AWAITING A
RELEASE SIGNAL
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Stress-Reducing Effects of Oxytocin in Rodents

• sedation and relaxation
• SNS activation
• blood pressure
• pain sensitivity
• cortisol secretion

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Hormonal control of monogamy?

Cushing BS, Carter CSJ Neuroendocrin. 1999
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Oxytocin and Attachment

• Pair-bonding
• Somatosensory stimulation
• Place and person preferences
• Conditioning effects
• Interactions with brain opioids
• Distress alleviation

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Brain-born oxytocin the hormone of intimacy

• Physical contact leads to release of oxytocin
  opioids.
• Distress alleviation, security, general feel
  good.
• Conditioning, addiction.

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Scientists are finding that, after all, love
really is down to a chemical addiction between
people
What is love? Biology does not have all the
answers.. But it does help us to ask new and
potentially important question.
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Oxytocin A Salivary Biomarker ?

• Using a sensitive enzyme immunoassay (EIA) and
  concentrated samples it is possible to detect
  reproducible changes in salivary oxytocin as a
  function of lactation and massage.
• Thus, measurements of biologically relevant
  changes in salivary oxytocin are possible.
• Saliva is a noninvasive source to monitor central
  neuroendocrine function.
• CARTER, CS Ann.N.Y. Acad. Sci. 2007.

A lab-test of monogamy?
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Synthesis and Release of AVP

• AVP synthesized in the hypothalamus in bodies of
  the Magnocellular nucleus in two paired nuclei
  that predominantly synthesize both AVP and
  oxytocin.
• Supraoptic nuclei
• Paraventricular nuclei
• Each neuron in these nuclei synthesize either
  oxytocin or AVP as a part of larger precursor
  molecule and stored as granules.
• Stores sufficient for 5 10 days of maximum need
  and 30 days of normal need.
• At least 4 neuronal tracts emerge from the nuclei
  and terminate in the
• Posterior pituitary release into circulation
• Median eminence secrete into the hypothalamus
• Third ventricle floor
• Brainstem, spinal cord

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Functions of AVP

• Reduces free water loss producing a concentrated
  urine.
• Average loss 2.5 3 L/day of fluid, 1.5 L from
  urine at an osmolality of 600 mOsm/kg.
• Integration of AVP and thirst keep plasma
  osmolality
• 280 290 mOsm/kg.
• Together with CRH controls ACTH release.
• May influence cognitive function.
• At supraphysiologic concentrations
• Contracts smooth muscle resulting in pressor
  activity.
• Activates liver release of glucose
• Increases lipolysis

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Metabolism and Actions of AVP

• Metabolized by liver and kidney.
• Lasts in circulation 15 to 20 minutes.
• Primary determinant of free water excretion.
• Major effect augment renal permeability
• Aquaporins (Benga, Agree, etc)

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AVP Mechanism of action

• Three specific G-protein-coupled receptors

V1a binding ß phospholipase C ß IP3,
Ca2 ß contraction of vascular and GI smooth
muscle
V1b binding ß phospholipase C ß IP3,
Ca2 ß potentiation of ACTH secretion by anterior
pituitary
V2 binding ß adenylate cyclase ß cAMP ß insertion
of aquaporin into luminal membrane of renal
medullary collecting ducts









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Regulation of AVP Release

• Osmotic Regulation
• Sodium
• Mannitol
• Urea
• Glucose
• Non-osmotic Regulation
• Hypotension
• Hypovolemia
• Nausea and vomiting
• Hypoglycemia
• Renin-angiotensin
• Pain, stress, emotions, hypoxia

Roughly 60 of the mass of the body is water,
and despite wide variation in the amount of water
taken in each day, body water content remains
incredibly stable.
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Diabetes Insipidus

• Diabetes insipidus results from loss of action of
  AVP (ADH) due to
• Deficiency of the hormone
• Inability of the hormone to act appropriately in
  the kidneys
• Increased clearance of AVP
• Causes excretion of large volume of dilute urine
  (hypotonic polyuria)
• Urine volume gt 30 50 ml/kg/d
• Urine osm lt 300 mOsm/kg
• Urine specific gravity lt 1.010

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Causes of Diabetes Insipidus

• Central DI
• Hypophysectomy
• Suprasellar surgeries
• Idiopathic
• Familial
• Tumors and cysts
• Histiocytosis
• Granulomas
• Infection
• Autoimmune
• Infarction
• Polydipsic DI
• Excess water drinking

• Nephrogenic DI
• Chronic renal disease
• Hypokalemia
• Protein starvation
• Hypercalcemia
• Sickle cell anemia
• Sjogrens syndrome
• Familial
• Drugs lithium, demeclocycline, cholchicine
• Congenital

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Laboratory Criteria of Diabetes Insipidus
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Man with a cough

• 66 year old, who has smoked cigarettes for 44
  years, complains of cough, weight loss, fatigue.
• PE B/P 120/80 pulse 78
• Lab Na 126 mmol/L
• Plasma Osm 270 mOsm/kg
• (280 -290)
• Urine Osm 680 mOsm/kg
• XRAY Chest XRAY shows lung mass

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SIADH

• Inappropriately high level of AVP for the plasma
  osmolality.
• Water retention with normal water intake
  resulting in hyponatremia and hypoosmolality.
• Urine inappropriately concentrated (sodium
  excretion gt20 mmol/day).
• Overall sodium balance is normal.

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Causes of SIADH

• Malignant lung disease
• Nonmalignant lung disease TBC, pneumonia
• Other tumors brain, lymphoma, pancreas,
  prostate, thymus
• Drugs clofibrate,chlorpropramide,
  thiazides,phenothiazines,vincristine, etc.
• Adrenal insufficiency, myxedema, anterior
  pituitary insufficiency

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Cerebral Salt Wasting Syndrome (CSWS)

• Following cerebral insults (head injury,
  subdural hematoma).
• Originally thought as part of SIADH.
• Characterised by hyponatremia, natriuresis,
  diuresis and hypovolemia.
• Associated with increased plasma BNP.
• In neurosurgical settings, it is a more common
  cause of hyponatremia and natriuresis than
  SIADH.
• Resolves spontaneously within 2 to 3 weeks.
• Responds well to intravenous saline.

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VASOPRESSIN IN THE BRAIN WHAT DOES IT DO THERE?
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NEUROHYPOPHYSEAL NEUROPEPTIDES AND LEARNING AND
MEMORY PROCESSES
Kovács et. al. 1976, 1984, 2005
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BRAIN-BORN VASOPRESSIN FRAGMENTSNO HORMONAL,
ENHANCED NEURONAL ACTIVITY
CLASSICAL RECEPTORS V1a, (V1b), OXT
(Vaccari et al, 1998)
Absorption-mediated endocytosis
pGlu4,Cyt6AVP-(4-8) pGlu4,Cyt6AVP-(4-9)
FRAGMENT RECEPTORS CLONED (Xiong et al, 1999
Nakayama et al, 2000)
Arg-His-Pro-pGlu4,Cyt6AVP-(4-9) (Tanabe et al,
1999)
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HUMAN FAMILIAL DIABETES INSIPIDUS MUTATION ON
THE PROHORMONE GENE

• T?G MUTATION (CHROMOSOME 20 NUCLEOTIDE 2110
  CODON 116),
• G?C REPLACEMENT NP85,
• AUTOSOMAL DOMINANT DISEASE,
• ENDOPLASMATIC RETICULUM,
• SLOW-ONSET NEURODEGENERATION
• (Nijenhuis és mtsai, 2001)

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Bruins J, Kovács GL, et al. Psychoneuroendocrinol
. 2005
HUMAN FAMILIAL NEUROHYPOPHYSEAL DIABETES
INSIPIDUS NEUROPSYCHOLOGICAL DISTURBANCES AND
ADAPTATION DISORDERS
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CONCLUSIONS