Neurohypophysis

Dra Roopa Mehta

Departamento de Endocrinología y Metabolismo

Instituto Nacional de Ciencias Médicas y Nutrición

Salvador Zubirán

Neurohypophysis

• The posterior pituitary arises from the forebrain (neural tissue) during development and lies below the hypothalamus with which it forms a structural and functional unit known as the neurohyopophysis

• Neurohypophysis consists of 3 parts:

1. Supraoptic and paraventricular nuclei of hypothalamus (contain cell bodies of the magnocellular neurons that synthesize and secrete Vasopressin (ADH) and Oxytocin)

Neurohypophysis

2. Hypothalamic- Neurohypophyseal nerve tract (axons of neurons)

3. Posterior pituitary (axons terminate on capillaries of the inferior hypophyseal artery)

Neurohypophysis

Vasopressin and Oxytocin

• The genes encoding ADH and oxytocin are on chrm 20• Synthesized as prohormones consisting of peptide

hormone + associated binding peptide or neurophysin (functions as carrier protein)

ADH + neurophysin II

Oxytocin + neurophysin I

• Transported in secretory granules via axoplasmic flow to nerve endings of the posterior pituitary

Vasopressin and Oxytocin

• In the secretory granules the prohormone undergoes further processing to produce mature peptide hormone + neurophysin (equimolar amounts)

• Action potentials that reach the nerve endings increase Ca influx- hormone secretion

• ADH and oxytocin circulate unbound to plasma proteins• They have a short half –life (5-15min)

Oxytocin

• In women, oxytocin contracts the pregnant uterus and also causes breast duct smooth muscle contraction leading to breast-milk ejection during breast feeding

• It is released in response to suckling and also to cervical dilatation during childbirth

• Oxytocin deficiency has no known adverse effects

ADH/ Vasopressin

• There are 3 vasopressin receptors:V1 Location: Vascular smooth muscle (Liver, platelets,

CNS)Action: Vasoconstriction (enhanced platelet adhesion, glycogenolysis, neurotransmitter)

V2 Location: Basolateral membrane of distal nephronAction: Antidiuresis via production and action of acquaporin 2

V3 Location: Pituitary corticotrophAction: Enhanced ACTH release (partly by enhancing action of CRH)

Functions of ADH

• The primary function of ADH is to regulate extracellular fluid volume by affecting renal handling of water. Its main action is to reduce free water clearance.

It is also a vasoconstrictor and pressor agent (hence, the name "vasopressin").

AVP acts on renal collecting ducts via V2 receptors to increase water permeability (cAMP-dependent mechanism), which leads to decreased urine formation (hence, the antidiuretic action of "antidiuretic hormone").

• A secondary function of ADH is vasoconstriction.  ADH binds to V1 receptors on vascular smooth muscle to cause vasoconstriction

Renal actions of ADH

• The major renal effect of ADH is to increase the water permeability of the luminal membrane of the collecting duct epithelium via the ADH sensitive water channels acquaporin 2 -results in concentrated urine (>osmolality)

• ADH binds to V2 receptor• This results in activation of adenyl cyclase via the stimulation of G-

alpha-s heterometric proteins,• The increased levels of cAMP activate protein kinase A and the

fusion of vesicles consisting of water channel proteins (AQP2) with the luminal membrane

• ADH also stimulates urea absorption in the descending limb and the inner medullary collecting duct via urea transporters

Stimuli for ADH secretion

• Plasma osmolality (> extracellular osmolality leading to cellular dehydration) is the most important stimulus

Plasma osmolality changes of as little as 1-2% are detected by hypothalamic osmoreceptors. Signals are transmitted to the supraoptic and paraventricular nuclei where ADH is synthesized.

The relationship between plasma osmolality and ADH concentration is linear. (Relationship lost with drinking- suppression of ADH release)

The threshold for ADH secretion is 284.3mOsm/kg.Urine is maximally concentrated (>800mOsm/kg) at a plasma osmolality of 295mOsm/kg

Stimuli for ADH secretion

Stimuli for ADH secretion

Stimuli for ADH secretion

• Decreased extracellular fluid volume (without change in osmolality) stimulates thirst and ADH secretion (e.g.hemorrhage)

Small decreases in volume have minimal effect on ADH levels; reductions >10% cause a marked increase in ADH secretion. (hyperbolic relationship-not linear)

These high levels do not cause further water conservation (max urinary concentrations are reached at much lower levels)

The high levels of ADH probably support blood pressure via V1 receptors

Hypovolemic stimulus to ADH release

Stimuli for ADH secretion

• Interaction of osmolality and volume• 2 mechanisms involved in hypovolemic stimulation of

ADH and thirst:1. Moderate reductions in blood volume result in

decreased stimulation of mechanoreceptors in the atria and central veins.

Atrial receptor firing normally inhibits the release of ADH by the posterior pituitary. With hypovolemia or decreased central venous pressure, the decreased firing of atrial stretch receptors leads to an increase in ADH release.

Stimuli for ADH secretion

More severe hypovolemia (hypotension <5-10mmHg) results in decreased firing of arterial baroreceptors. This leads to enhanced sympathetic activity, which increases ADH release.

2. Hypovolemia stimulates renin secretion and angiotensin formation. Angiotensin II also stimulates thirst and ADH secretion

Stimuli for ADH secretion

• Regulation of water balance involves interaction between osmotic and volume stimuli

• For a given increase in osmolality, the increase in plasma ADH will be greater in hypovolemic than in normovolemic states

• Other factors known to increase ADH levels include nausea, pain and surgery

Osmoregulation of ADH release

Stimuli for ADH secretion

Diabetes Insipidus

• Characterized by deficient ADH action and the production of large amounts of dilute urine

• Must be differentiated from other polyuric states such as primary polydipsia and osmotic diuresis

• The passage of large volumes (>3L/d) of dilute urine (osmolality <300mOsm/kg)

Results in cellular and extracellular dehydration which stimulate thirst and cause polydipsia

Classification

1. Cranial DI:

Deficiency of ADH- complete or partial

2. Nephrogenic DI:

Renal resistance to ADH

3. Primary polydipsia:

Polyuria due to excessive drinking (suppressed ADH due to <plasma osmolality)- psychological cause

Causes of central DI

• 10% of ADH cells necessary to maintain water balance• Familial (5%): Autosomal dominant (ADH gene)

DIDMOAD syndrome (DI, DM, optic atrophy, deafness)

• Acquired: Trauma (head injury, hypothalamic/pituitary surgery)

Tumors (craniopharyngiomas, pituitary mets)

Inflammatory conditions (sarcoidosis, TB, histiocytosis, lymphocytic hypophysitis)

Infections (meningitis, encephalitis)

Vascular (Sheehans, Sickle cell disease)

Idiopathic

Causes of central DI

• Trauma:

DI due to head trauma often follows triphasic course:

1. Transient DI (axonal damage)- 24hrs

2. Antidiuresis- SIADH (release of pre-synthesized ADH)- 5-7days

3. Recovery or permanent CDI

Causes of nephrogenic DI

• Familial: X-linked recessive (vasopressin receptor gene)

autosomal recessive (acquaporin-2 gene)

• Acquired: drugs (lithium)

metabolic (hypokalemia, hypercalcemia)

chronic renal disease (PCO, obstructive uropathy)

systemic disorders (amyloidosis)

Presentation

• Adults: polyuria, nocturia, thirst• Children: polyuria, enuresis, and failure to thrive

• Exclude cortisol deficiency (failure to excrete water load) as this may mask cranial DI

• DI may worsen in pregnancy due to placental breakdown (vasopressinase) of circulating vasopressin

Investigation

• Confirm DI

• Classify DI:

(central, nephrogenic, primary polydipsia)

• Establish etiology: if CDI is suspected, an MRI of hypothalamus and pituitary. There is a loss of the normal hyperintense signal of the posterior pituitary on T1-weighted images

MRI in CDI

Investigation for CDI

• Careful history. Confirm large urine output.• Prediliction for cold beverages• Exclude hyperglycemia (DM), hypokalemia,

hypercalcemia and significant renal disease• Measure electrolytes + plasma and urine osmolality

In CDI and NDI urine is less concentrated than plasma• Water deprivation test• Saline infusion test• Therapeutic trial of vasopressin• ADH measurement

Water deprivation test

• Patient is allowed fluids overnight. Avoid caffeine and tobacco.

• Patient is then denied fluids for 4-18 hours or until 5% loss of body weight

• Basal weight; Basal plasma and urine osmolality and urine volume. Repeat hourly. (basal ADH)

• Supervise patient closely to avoid nondisclosed drinking• Continue until 3 consecutive urine osmolalities vary by

less than 30mOsm/kg (reaches plateau)- measure plasma osmolality (measure ADH)

• Inject 2ug i/m DDAVP and measure plasma and urine osmolality an hour after

Interpretation

• Healthy: water deprivation should stimulate ADH secretion and maximal urine concentration.

Additional ADH will not lead to more than a 10% increase in urine osmolality

DiagnosisUosm

After fluid deprivation

Uosm

After DDAVP

CDI<300 + plasma Osm >290

>800

NDI <300 <300

Primary polydipsia

>800 + no rise in plasma osmolality

>800

Partial DI or polydipsia

300-800 <800

Hypertonic saline infusion

• Differentiates partial DI from PPD

• Measurement of ADH during infusion of hypertonic 5% sodium chloride 0.1ml/kg per min for 1-2 hours

• Measure ADH once serum osm and sodium are above 295mOsm/kg and 145mEq/L

If nausea is present – test interpretable

Hypertonic saline infusion

• CDI: Undetectable ADH during the progressive hyperosmolar stress, or values fall to the right of the normogram relating ADH to plasma osmolality

• NDI: ADH inappropriately high for plasma osmolality

• PPD: Relationship of ADH to plasma osmolality is normal

Hypertonic stress testing

Therapeutic Trial

• To differentiate partial CDI and partial NDI therapeutic trial of ADH:

10-25mcg/ day of intranasal DDAVP for 2-4 days

Monitor plasma Na

CDI: improvement in polyuria and polydipsia

remain normonatremic

NDI: No response

PPD: Progressive dilutional hyponatremia

Influence of endocrine disease

• The diagnosis of DI is difficult in presence of anterior pituitary disease.

• Low or absent levels of glucocorticoids or thyroid hormones reduce fluid delivery to the kidneys (<renal perfusion)- and thus reduce urine flow.

• Such patients retain a water load .• Even if DI is present, coincident glucocorticoid or thyroid

hormone deficiency may mask the polyuria

Treatment of CDI

• The treatment of choice for those with significant symptoms is the synthetic, long-acting ADH analogue DDAVP:

intranasal spray (5-100 mcg daily); parenteral injection (0.1-2.0 mcg daily); or oral (100-1000 mcg daily), in divided doses.

• There is wide individual variation in the dose required to control symptoms.

• Dilutional hyponatremia is the most serious potential adverse effect. This can be avoided by omitting treatment on a regular basis (perhaps weekly), to allow a

short period of breakthrough polyuria and thirst.

Primary polydipsia

• PPD is a polyuric syndrome secondary to excess fluid intake.

• Though structural abnormalities may be the cause, it is generally a manifestation of primary hyperdipsia, psychiatric disease, or secondary to drug effects. It can be associated with several abnormalities of thirst perception.

• A low osmotic threshold for thirst. (<threshold for ADH- constant hypotonic polyuria because serum osm below that for ADH release)

• An exaggerated thirst response to osmotic challenge. • An inability to suppress thirst at low osmolalities.

Treat underlying cause. Reduced fluid intake is only tx

Syndrome of inappropriate ADH secretion (SIADH)

• ADH levels inappropriately high for plasma osmolality- water retention + normal water intake

• Hyponatremia (Na < 130mmol/l) (occurs in 15% of

hospitalized patients) [Euvolemic hyponatremia]• Low serum osmolality (<280mOsm/kg)• Inappropriately concentrated urine (>100mOsm/kg)

Submaximally diluted urine due to inadequately suppressed ADH (urine osm >plasma osm)

• Urinary sodium >20mEq/l (water retention leads to secretion of ANP by the atria- natriuresis)

Hyponatremia

Pathophysiology of hyponatremia in SIADH

Patterns of abnormal ADH secretion

• A Wide fluctuations in plasma VP concentration independent of plasma osmolality (35%)

• B Osmotic threshold for VP release subnormal. Osmoregulation around subnormal osmolar set point(30%)

• C Failure to suppress VP release at low plasma osmolality Normal response to osmotic stimulation

• D Normal osmoregulated VP release. Unable to excrete water load. (<10%)

Causes of SIADH

Clinical manifestations

• Headache • Nausea • Vomiting • Muscle cramps • Lethargy • Disorientation  • Seizure • Coma • Osmotic demyelination • Brain-stem herniation • Death

Diagnostic criteria for SIADH

Hyponatraemia with appropriately low plasma osmolality

Urine osmolality greater than plasma osmolality

Renal sodium excretion * 20 mmoles/l

Absence of hypotension, hypovolaemia and oedema-forming states

Normal renal and adrenal function

Central pontine myelinolysis

• Changes in brain volume (in response to changes in osmolar gradient across the blood-brain barrier) as serum sodium changes during treatment can trigger CNS demyelination.

• This osmotic demyelination is a rare but serious complication of chronic hyponatraemia and its treatment.

• It can develop within 1-4 days of rapid (>12 mmols per 24 hours) correction of plasma sodium, irrespective of the method employed to achieve it.

Treatment

• Immediate osmotherapy with hypertonic saline is indicated if the patient has severe symptoms of hyponatremia (seizures, coma +/- signs of herniation) + serum sodium < 120 meq/L + acute hyponatremia

• Chronic hyponatremia is more likely to lead to cerebral demyelinization if corrected too rapidly.

• Acute hyponatremia may lead to cerebral edema if not corrected quickly

The goal of therapy is to raise serum sodium at a rate less than 0.5mEq/l per hour up to 125mEq/l, then fluid restriction is applied

Acute symptomatic hyponatremia

• If the patient is actively seizing or has signs of a markedly increased ICP, hypertonic 3% saline solution should initially be administered at a rate of 3 - 4 cc/kg/hour for 30 - 60 minutes (which usually causes a serum sodium increase of 4 - 6 mEq/L/hour) => follow-up with hypertonic saline at 1 - 2 ml/kg/hour prn + measure the serum sodium hourly at first, and then every 2 - 3 hours

• A lower initial dose of hypertonic saline (1 - 2 ml/kg/hour) is recommended if the patient has severe neurological symptoms (confusion or lethargy), but is not actively seizing or herniating

Acute symptomatic hyponatremia

• Avoid increasing the serum sodium > 1 - 2 meq/hour for more than a few hours after the immediate (first one-hour) corrective phase of therapy => then lower the hypertonic saline infusion rate to < 0.5cc/kg/hour to prevent the serum sodium concentration from increasing faster than 0.5 meq/L/hour

• A loop diuretic can be given to enhance free water excretion

• The total daily increase in the serum sodium should be limited to < 12 meq/24 hours

• The aim is a maximum final serum sodium concentration of 120 meq/L in the first 24 hours

Chronic asymptomatic hyponatremia

• If the patient is asymptomatic or minimally symptomatic, or if the serum sodium is > 120 meq/L => osmotherapy is not indicated and the emphasis should be targeted toward correcting the underlying condition

• Fluid restriction is applied- 800-1000ml/d