Posterior Pituitary- MBChB IV

Department of Chemical Pathology

2023
Learning Outcomes:
• Understand the anatomy and blood supply of the hypothalamus and
pituitary gland and how the two are related
• Understand the factors that control the release of ADH

• Describe the major causes of vasopressin deficiency

• Demonstrate a thorough understanding of the pathophysiology, associated

causes, classification and biochemical workup of Diabetes Insipidus

• Develop an approach to the investigation of Polyuria

• Demonstrate a thorough understanding of the pathophysiology, associated

causes and biochemical workup of Diabetes Insipidus

• Describe the major actions of oxytocin and factors responsible for its release
 Hypothalamus- Basic Anatomy

.
The hypothalamus, located on the ventral surface of the brain, around the third ventricle

Responsible for controlling pituitary hormone secretion.

It secretes peptide hormones, also known as hypothalamic releasing factors, either:

● Into the short private portal system to directly impinge on the anterior pituitary (eg.
TRH, GnRH), or
●Directly into the general circulation (eg. oxytocin, vasopressin)
 Pituitary Gland

Lies at the base of the brain below the hypothalamus.

Is about the size of a pea

Lies behind the nasal bone

 Development and Anatomy of the Pituitary Gland

●The hypophysis is an amalgam of two tissues.

●Endodermal that grows upward from the roof of the mouth to form the Rathke's
pouch and will develop into the anterior pituitary or adenohypophysis.

● Neuroectodermal tissue evaginates ventrally from the diencephalon of the developing

brain to form the posterior pituitary or neurohypophysis.

●Ultimately, the two tissues grow into one another and become tightly apposed, but their
structure remains distinctly different.
 Pituitary Gland

The pituitary is the master gland controlling many metabolic processes.

Also called hypophysis- a ductless gland that secretes hormones directly into the bloodstream.

The hypophysis is composed of:

●The average weight is between 500-900mg (with the female gland usually heavier
than the male).

●Measuring 10-17mm: side to side, 5-15mm: front to back and 5-10mm top to
bottom.

●An important anatomical relation to the pituitary gland is the optic chiasm, which
lies just above the pituitary fossa.

● Expanding lesions in the pituitary or hypothalamus can cause visual field defects
 Pituitary Gland

Important Anatomical relations ***

 Blood Supply

●The blood supply to the hypothalamus and pituitary is by the circle of Willis at the base
of the brain.

●The superior hypophyseal arteries which arise from the internal carotids.

●Portal vessels run down the pituitary stalk (infundibulum) to the pituitary gland.

●This system is known as the hypothalamo-hypophysial portal system.

●The hypophyseal portal system - blood vessels in the microcirculation at the base of the
brain, connecting the hypothalamus with the anterior pituitary quickly transports and
exchanges hormones between the hypothalamus and anterior pituitary gland.
Blood Supply
 Pituitary = The Master gland

• The adenohypophysis/anterior lobe ≈75% by mass

• The neurohypophysis/posterior lobe ≈25% by mass

- not a true gland, but a temporary storage for hormones synthesized in the hypothalamus
Posterior pituitary /neurohypophysis hormones

● Antidiuretic hormone (ADH) /Vasopressin and Oxytocin are secreted from

the neurohypophysis.

● Cell bodies (site of synthesis) is located in hypothalamic supraoptic and

paraventricular nuclei.

● Synthesised as prohormones  then processed within vesicles to mature

peptides (ADH & Oxytocin) (nanopeptides – 9AAs)

● Their difference is only on two amino acids: Similar in primary structure but
very different biological and immunological properties
 Release of hormones

●Vesicles (containing hormones) travel from cell bodies in the hypothalamus, down the nerve tract to the
nerve terminals in the posterior pituitary where they are stored

●Hormones are released from vesicles into the circulation in response to:
- electrical activity in the nerve terminals
- calcium dependent exocytosis of the hormones from the nerve terminals

●Hormones circulate unbound to plasma proteins and have a short half-life (5-15 minutes)
Antidiuretic hormone (ADH)
Vasopressin
Arginine Vasopressin (AVP)
Biochemistry ADH

● At the physiologic pH of plasma, ADH and oxytocin circulate mainly as unbound (free)
hormones.

• Three receptor subtypes mediate the actions of ADH:

Receptor Type Site Effect

V1a CVS Vasoconstriction
V1b Anterior Pituitary ACTH release
V2 Distal Renal Water
Collecting Tubules Reabsorption
 Regulation of ADH Release

Factors stimulating release: Factors inhibiting release:

↑ plasma osmolality (>280mOsm/kg) ↓ plasma osmolality

Hypovolemia (↓ECF volume) ↑ ECF volume

Pain, emotion, stress, exercise, surgery Alcohol

Nausea & vomiting Cortisol

Drugs e.g., nicotine, opiates, barbiturates, Thyroid hormone

histamine

Standing ANP

Angiotensin II
 Two major stimuli for ADH release

i) Osmolality and ii) Volume

1) Increased plasma osmolality (dehydration)  stimulate osmoreceptors leading to increased ADH

- Relationship between plasma osmolality and ADH is linear
- Threshold for ADH release is 284.3 mOsm/kg
Osmolality and ADH Regulation
 ii) Volume and Regulation of ADH

Reduced blood volume (≥ 10%)→ stimulation of baroreceptors in the great arteries (aorta & carotids)
& right atrium → reduction of tonic inhibitory pulses from the left atrium → ↑ADH.
 ADH related disorders

Deficiency of ADH Excessive Secretion of ADH

Diabetes Insipidus (DI) Syndrome of Inappropriate
ADH (SIADH)
Diabetes Insipidus (DI)
 Disorders of ADH Release or Action

Characterized by:

 Polyuria:
Urine (>3L/day or >2L/day in adults and children, respectively)
Dilute urine/ hypotonic urine (osm <300mOsm/kg)
• nocturia
Polydipsia
• tendency to dehydration
Thirst
• stimulation of thirst center
Pathophysiology of Polyuria

Three mechanisms:
1. Insufficient osmoregulated ADH – Central/Cranial/Neurogenic DI
2. Complete or partial renal resistance to the action of ADH – Nephrogenic DI
3. Habitual excessive fluid drinking – Primary Polydipsia
i. Psychiatric Illness – Psychogenic DI
ii. Abnormality in the thirst mechanism – Dipsogenic DI
Central Diabetes Insipidus

• Most common
• Mainly secondary to irreversible destruction of >80% ADH producing neurons
(hypothalamic &/ pituitary problem), genetic causes reported

• Deficiency of ADH (partial/ complete)

Causes
• Hereditary (5%): genetic mutation of vasopressin gene autosomal dominant or recessive
or X-linked recessive

• Acquired: - trauma* (head injury)

- surgery* (hypothalamic/ pituitary surgery)
- tumors (1⁰ e.g. craniopharyngioma, 2⁰ tumors) **
- infections (meningitis, encephalitis)
- granulomatous disease (TB, sarcoidosis)
- vascular (Sheehans disease)****
- autoimmune
- idiopathic * may be transient, permanent or triphasic
Sheehan's syndrome,
Decreased functioning of the pituitary gland), caused by ischemic necrosis due to blood loss and
hypovolemic shock during and after childbirth
Nephrogenic DI

Caused by nonresponse/resistance of kidney to ADH

• Most common form is congenital/ hereditary

Causes

• Hereditary (90%):
NDI1: X-linked recessive (vasopressin receptor gene mutation)
NDI2: Autosomal recessive (acquaporin-2 gene mutation)
• Acquired (10%):
- metabolic (hypokalaemia, hypercalcemia)
- drugs (lithium, demeclocycline, amphoterin B, colchicine)
- renal disease (acute/ chronic renal failure, pyelonephritis, polycystic disease,
obstructive uropathy)
- amyloidosis
- sickle cell disease, ischaemia
- Sjogren syndrome
Clinical features of DI

● Adults: polyuria, nocturia, dehydration, thirst & polydipsia

● Children: polyuria, enuresis, anorexia, fatiguability, linear growth failure

● Infants: thirst and polyuria cannot be verbalised: inconsolable cry, unusually wet diapers,
frequent need to nurse, dry skin with cool extremities, failure to thrive, growth failure

● Others features: lack of sweating, constipation, changes in the mental status, shock,
signs & symptoms of underlying disease
 Investigations
Aim:

● Confirm and classify DI:

1. 24hr urine collection – assess volume

2. Urine & plasma osmolality (simultaneous)
3. Urine specific gravity
4. Blood electrolytes (sodium)
5. Blood glucose (r/o DM)
6. Water deprivation test
7. Therapeutic trial of vasopressin

● Establish etiology e.g., if CDI is suspected  MRI of hypothalamus and pituitary

https://doi.org/10.1016/j.ando.2012.03.030
Understand the mechanism behind the results
Water deprivation test
 Water deprivation test (Deprive the patient water)
● Indication: confirm or rule DI

● Contraindication: DM, hypercalcemia, hypokalemia, chronic renal failure,

hypoadrenalism, hypothyroidism, drugs therapy e.g., lithium, ability to concentrate
urine (urine osm > 750mOsm/kg)

● Principle:
Essentially a biological assay for vasopressin

Involves adequate dehydration to stimulate maximal stimulation of ADH for

diagnosis.

Water restriction  dehydration  ADH release  renal water reabsorption 

concentrated urine while plasma osmolality does not rise >295mOsm/kg).

In Diabetes Insipidus this mechanism fails  dilute urine + ↑ plasma osmolality

• Side effect: severe dehydration in patients with true DI, monitor closely
Water deprivation test Procedure

• Baseline weight and urine osmolality

• Patient is then deprived of water

• Collect urine and measure urine osmolality and body weight hourly.

• If 2 sequential i) urine-osm vary by <30 mOsm/ kg

or ii) the total body weight loss falls by > 3%

administer 5U of aqueous ADH/ desmopressin s/c

• Obtain a final urine specimen for osmolality 60 min later

(time required to achieve maximal urinary concentration: 4-18hrs)
 Interpretation of Water deprivation test

• In Normal and psychogenic polydipsia, urine osmolality rises progressively

during water deprivation until it reaches the high hundreds (700-800mosmol/kg).

• Plasma [Na+] and body weight show negligible change.

• In diabetes insipidus (DI), urine osmolality plateaus out at a much lower value
(eg. 200-300 mosmol/kg), depending on the severity.

• There is a progressive increase of plasma Na+ and loss of body weight, and
patients soon become thirsty and distressed from dehydration.

• If the DI is neurogenic, urine osmolality increases after ADH is given,

whereas in nephrogenic DI, it remains unchanged.
Interpretation of Water deprivation test

Urine Osmolality (mOmos/kg)

Diagnosis After Fluid Depravation After Desmopressin

Neurogenic DI <300 >800

Nephrogenic DI <300 <300

Partial DI or Polydipsia 300-800 <800

Primary Polydipsia >800 >800

 Treatment
1. Fluid replacement
- adequate access to water to replace losses
- when water intake is inadequate  hypernatremia: dextrose + water or hypo-osmolar
IV fluids
- monitor fluid output & input & plasma sodium

2. Drug therapy
a) Central DI: desmopressin non hormonal drug if incomplete response to
desmopressin e.g. thiazides, chlopropamine, clofibrate, indomethacin)
b) Nephrogenic DI: - low sodium diet - thiazide diuretics + potassium supplements or
thiazides + amiloride – indomethacin

3. Monitor 24-hr urine volume, serum & urine electrolytes & osmolality, urine-SG

4. Treat the underlying cause if possible

5. Primary Polydipsia – psychological and behavioural treatment

Flow chart for the investigations of polyuria
Syndrome of inappropriate ADH (SIADH)
Syndrome of inappropriate ADH (SIADH)

Syndrome of inappropriate ADH (SIADH) – Continued release of ADH when low plasma
osmolality  suppress ADH secretion.

Features of SIADH
• Hypotonic hyponatraemia (H2O retention)
• Hypo-osmolality ((<275 mosm/kg) resulting from inappropriate SIADH
• Elevated urine Na (>20 mEq/L) –Natriuresis (↑GFR, suppressed
aldosterone secretion and ANP)
• Urine osmolality inappropriately elevated in relation to the low plasma
osmolality plasma osmolality
• Absence of oedema
• normal renal and adrenal function.
When to suspect SIADH?
Any patient with hyponatraemia who excretes urine that is hypertonic relative to the
plasma.
 Syndrome of inappropriate ADH (SIADH)

• Causes of SIADH:

• Intracranial pathology (head injury, haemorrhage, meningitis, or brain tumour)

resulting in direct stimulation of hypothalamic ADH release.

• Pulmonary pathology (pneumonia, TB, assisted ventilation), where volume

receptors in the pulmonary vascular bed falsely report a message of vascular
depletion to the hypothalamus.

• Ectopic production of ADH by tumours, particularly bronchial carcinomas.

• Cortisol deficiency – since these hormones antagonize ADH, a deficiency of either

will result in unopposed ADH action.

• Pain, from trauma or surgery, stimulates ADH release.

Syndrome of inappropriate ADH (SIADH)
 SIADH and Absence of Oedema
• Patients with SIADH are “over-hydrated” but do not become oedematous.

• Retained water is shared between the ECF and ICF but ECF expansion is
eventually limited by the release of atrial natriuretic factor (ANF ) from cardiac
atria, which promotes a saline diuresis.

• ANF acts to reduce plasma volume by at least 3 mechanisms: increased renal

excretion of salt and water, vasodilation, and increased vascular permeability.

• Their major problem is hyponatraemia, leading to cerebral oedema and

consequent depressed level of consciousness.

• The more rapid the onset of hyponatraemia, the more severe is the cerebral
oedema, since slow onset allows the brain time to decrease its osmolyte content.

• Urine is typically inappropriately concentrated despite low plasma osmolality, and

its [Na+] is high in the face of hyponatraemia (the effect of ANF).
 Atrial Natriuretic Peptide (ANP) in water balance

The RAAs System has a dual effect- reduction in Renin

•Low Angiotensin II  results in vasodilation  low Bp

•Low Aldosterone (mineralocorticoid) results in salt (natriuresis)

Current Psychiatry. 2021 September;20(9):51-56
Oxytocin
Oxytocin

Site of synthesis:

● Mainly PVN of Hypothalamus ●1/6th SON of Hypothalamus

Actions

1) Contraction of smooth muscles of the uterus  enhance labour

2) Contraction of mammary gland myoepithelial cells of the alveoli and the ducts
 ejection of milk

3) In men  ↑ejaculation

** Oxytocin  releasing or ejection of milk

Prolactin  synthesis and production of milk.
 Mechanism of action
Action via G Protein coupled receptors

Factors stimulating release: Factors inhibiting release:

Suckling Psychological or emotional factors-

fear, stress, anxiety
Emotions

Sight/Sound of baby’s cry Drugs- alcohol

Dilation of the cervix (Parturition)

During coitus

Hormones:
A. Progesterone ↓ uterine sensitivity to oxytocin

A. Estrogen ↑ uterine sensitivity to oxytocin

Parturition Reflex
Neural reflex and Milk Production
 Sources and References

https://www.google.co.za/search?q=treatment+of+siadh
Cardiovascular physiology concepts Richard E Klabunde
https://www.google.co.za/search?q=osmolarity+vs+osmolality&source
https://www.google.co.za/search?q=osmometer&tbm
https://www.google.co.za/search?q=approach+to+hyponatremia
https://www.google.co.za/search?q=approach+to+hypernatremia
Clinical Chemistry in Diagnosis and Treatment- Sixth Edition –Zilva , Pannall and
Mayne
Clinical Chemistry -Fourth Edition William J Marshall
Dr. B Sedumedi – SMU 4th Chemical Pathology Notes
Posterior Pituitary (Neurohypophysis). Samuel Dagogo-Jack, M.D.