Lecture 6: Posterior Pituitary Gland

Location of The Posterior Pituitary Gland

• Located below the hypothalamus and optic chiasm in the sella turcica (ring of bone)

Hypothalamic Regulation of The PPG

• Long magnocellular neurons extend down from the hypothalamus down the pituitary stalk and into the PPG lobe

• Axons synapse with blood vessels in the posterior lobe to release hormones into the general circulation

Posterior Pituitary Hormones

• 9 amino acid peptides are synthesised in the hypothalamus and transported down the axons of the posterior pituitary for secretion into the blood

• 2 types

  • ADH/ Vasopressin

  • Oxytocin

Difference Between Oxytocin and Vasopressin

• Differ in two of the nine amino acids

  • Vasopressin: Phe and Arg

  • Oxytocin: Leu and Ile

• Pre/Pro- hormones also differ

Vincent Du Vigneaud

• Nobel Laureate 1955:

• First synthesis of polypeptide hormone (oxytocin)

Synthesis of Oxytocin And Vasopressin

• Occurs within supraoptic and paraventricular nuclei of the hypothalamus

•  Cells that produce the hormones are both found in these areas and will either produce oxytocin or vasopressin respectively

  • Occasionally (1%) of the cells in that area will produce both hormones – due to structural similarity

• Synthesised as large pre-cursor molecules and packaged into granules in separate neurons

Processing of PPG Hormones

• Occurs en route to the PPG to produce the active hormones and Neurophysins (carrier protein)

• Occurs as granules move down the axon, with the peptide chopped into 2 halfs to form the hormone and neurophysin

Neurophysin

• Physiological role unknown

• Produced following the processing of the hormone pre-cursors

  • Neurophysin I – Oxytocin  

  • Neurophysin II – ADH

      May support transport

• Remains bound to hormone until release into the circulation

  • Carrier and hormone bound whilst processed down the axon

Receptor-Mediated Actions of Oxytocin

• A peptide hormone and will bind to receptors on the cell surface     

  • via G-protein-linked cell-surface receptors      

• Increase in Pi turnover      

• Mobilisation of intracellular Ca 2+  

  • Second signalling mechanism

Physiological Effects of Oxytocin

• Stimulaiton of Milk Ejection

• Stimulation of Uterine Muscle in Labor

• Establishment of Maternal Behaviour

Ductal Network of The Breast

• Responsible for the transport of milk from where it is produced to where it is released

Alveoli/ Loubles of The Mammary Gland

• Small sacs that contain milk

• Site of ejection for consumption following the contraction

• Are grouped together to secrete into the the same duct

Myoepithelium

• Smooth muscle surronding groups of alveoli

• A prominent target for oxytocin - stimulates contraction, causing milk to be ejected into the smooth muscle

• Contains a specific receptor

Oxytocin + Receptor of Myoepithelial

• Once bound, it causes an increase in Ca2+ → Causes muscle to contract and squeeze the alveoli

• Milk then passes into the ducts and nipple - allows the baby to feed

Reflex Arc in Nursing (Oxytocin)

• Action is relayed within a few milliseconds via a spinal reflex arc to the brain

• Sensory neurons in the breast signal the hypothalamus, via neurons synapsing the magnocellular neurons to release oxytocin and stimulate contraction and expulsion of milk

  • stimulates oxytocin-secreting neurons causing the release of oxytocin and contraction of myoepithelial cells.

Factors Affecting Nursing Reflex Arc

• Fear, anxiety, pain and alcohol inhibit the release of oxytocin

Neural Connections of The Nipple

• Sensory neurones in the breast and surrounding vascular system are in synaptic contact with neurosecretory neurones within the hypothalamus,

  • signal hypothalamus to release oxytocin in response to signal of suckling

Changes in the Later Stages of Gestation

• Increase in the number of oxytocin receptors on the uterine smooth muscle

  • Uterus more sensitive to oxytocin, which helps to trigger and maintain labor contractions.

Initation of Labour

• Oxytocin released in response to the foetal stimulation of the cervix

  • Babies head presses down on the cervix  during labour

• Pressure on the cervix sends a signal to the brain to cause the release of oxytocin that will then bind to receptors on the smooth muscle and cause further contraction

Facilitation of Birth

• Oxytocin released during labour and enhances the contraction of the uterine smooth muscle

  • Released in waves by the hypothalamus

• Binds to receptors in the uterus, stimulating contraction

• Causes the baby to push on the cervix - stimulates sensory neurons to release more oxytocin

• Further oxytocin secretion results in stronger contractions to allow baby ejection

Pitocin

• Synthetic form of oxytocin used in labour, if uterine contractions are insufficient to complete delivery

  • Cautions when administering - risk of rupturing uterus

• 25% use for labour induction

• 50% use for placenta expulsion

Dangers of Oxytocin/ Pitocin Use

• Causes contraction to come about too quickly and if the uterine muscle squeezes too hard on the umbilical cord,

• Prevents blood flow to the baby – block O2 supply –

  • devastating effect - CP

Atosiban

• Oxytocin antagonist

• Used to inhibit premature labour - slows down contractions

Role of Oxytocin in Parturiton

• Acts within the brain to assist the establishment of maternal behaviour

  • Vital in successful reproduction

• HIgh levels of hormone within the breast milk may contribute the the mutual bonding of the offspring to mother

  • Two-way process

Problem of Pictocin/ Synthetic Oxytocin

• Doesn’t cross BBB and enter the brain

• Remains in the circulation and will act on the receptors in the uterine muscle

  • May hinder the establishment of maternal behaviour

Disruption of Oxytocin Gene in Mice

• Display normal maternal behaviour but show deficits in milk ejection and subtle changes in social behaviour

  • No stimulation to smooth muscle around alveoli in breast tissue

Evidence of Oxytocin’s Role In Maternal Behaviour

• 2 Experiments

  • Infusion of oxytocin into the brains of virgin rats rapidly induces maternal behaviour → lick and groom pups

  • Administration of antibodies to oxytocin or oxytocin antagonists into the brain will prevent mother rats from accepting their pups → no tactile stimulation

Necessity of Oxytocin in Maternal Behaviour

• A major facilitator of parturition and maternal behaviour rather than an absolute initiator of these processes

Role of Oxytocin in Males

• Synthesised in the testes and hypothalamus

• May facilitate sperm transport within the male reproductive system,

  • present in seminal fluid      

• Effects on social behaviour - paternal behaviour

Effect of Acute Stress on Oxytocin Secretion

• Catecholamines released from the adrenal gland in response to many types of stress decrease oxytocin secretion

• Assessed in dairy farms – looked at the effect of music on milk production

  • Calming music - ­ milk production

  • Rock music - ¯ milk production – produced more stress hormones

Effect of Sex Steroids on Oxytocin Secretion

• Reduce both the production of and response to oxytocin  

  • Burst of oxytocin released at birth is triggered in part by abruptly declining concentrations of progesterone.

Effects of Oxytocin on Wider Behaviour

• Increase in trust and interpersonal relationships

  • associated with the ability to maintain healthy interpersonal relationships and healthy psychological boundaries with other people.

    • Results somewhat controversial

Clinical Uses of Oxytocin

• Autistic Spectrum Disorder – effects have been disputed – very subtle;

  • dependent on measurement of effects

• Anorexia

• Anxiety

• Long-term effects not clear

  • Important consideration for paediatric administration

• Clinical trials ongoing

Actions of Vasopressin (ADH)

• Hormones bind to receptors on cells in the collecting ducts of the kidney and promote reabsorption of water back into the circulation

• Stimulates the synthesis of aquaporins

     

Absense of Vasopressin (ADH)

• Collecting ducts are virtually impermeable to water, which then flows out as urine

  • hormone required for the absorption of water in the blood

Areas of The Nephron Sensitive to ADH

• Receptors are located in the distal convoluted tubule and collecting ducts

• Receptors present will bind to ADH to promote the reabsoprtion of water into the blood stream

Aquaporins

• Synthesised from Aquaporin-2 Gene in response to vasopressin (ADH) and are inserted into the membranes of kidney tubule cell

• Transport solute free water through the tubual cells of the kideny back into the blood

  • Causes “dilution” of the blood (i.e. a decrease in plasma osmolality) and an increased osmolality of urine.

2 Sides of The Nephron

• Apical membrane - faces the lumen

  • Lumen - site where urine passes thorugh

• Basolateral membrane - faces blood

Aquaporins and Water Retention: Well Hydrated

• Water reabsorption is not required

  • Water passes through the kidney and out as the urine

Aquaporins and Water Retention: Less Hydrated:

• Water absorption is required        

• Vasopressin is released and binds to the V2 receptor (Gs receptor) of the kidney cell and causes an increase in cAMP,

• This results in Aquaporin-2 channels being inserted into the apical membrane to allow the passage of water from the lumen into the kidney cell

• Aquaporin 1 and 3 are constitutively present on the basolateral side of the membrane allowing the movement of water from inside the kidney cell into the blood 

  • Less water passes through the kidney and out as urine

Osmolaltiy

• The concentration of solutes in the blood

  • Detected by hypothalamic osmoreceptor

• Most important variable in regulating Vasopressin/ ADH secretion

Increased Plasma Osmolaltiy

• Increasing osmolality is sensed by hypothalamic osmoreceptors, which stimulate secretion from the hypothalamic neurons that produce vasopressin

Decreased Plasma Osmolaltiy

• Vasopressin secretion is supressed

Effect of Water Deficit

• decreases plasma volume → activation of baroreceptors in the aortic arch and carotid sinus

• increased extracellular osmolality – increase solute concentration in plasma → triggers hypothalamic osmoreceptors

• Result in an ADH secretion, causing the insertion of the aquaporin 2 channels, to increase permeability of the kidney to increase water reabsorption

Effect of Water Reabsoprtion

• Decreases plasma osmolality and increases plasma volume

  • acts as a negative feedback loop and stops ADH secretion

Factors Increasing Vasopressin/ ADH Secretion

• Angiotensin, pain, trauma, anxiety, nausea, vomiting, haemorrhagic blood loss, drugs such as nicotine and morphine

  • Situations of water preservation

Factors Decreasing Vasopressin/ ADH Secretoin

• Ethyl alcohol

  • dehydration/ hangover

• Caffeine

Effect of Vasopressin/ ADH on Vascular Systems

• High concentrations cause widespread constriction of arteriole

  • Leads to increased arterial pressure in some species

• It was for this effect that the name was coined

• Minor pressor effects are seen e.g. in response to haemorrhage in humans

Osmotic Control of Vasopressin Secretion E.g. In A Dessert

• Loss of body water through sweat

• Loss of water results in a concentration of blood solutes - plasma osmolality increases.

• Urine production not maintained and ADH is secreted, allowing almost all the water that would be lost in urine to be reabsorbed and conserved

Relationship Between Vasopressin Secretion and Thirst

• Both stimulated by the hypothalamic osmoreceptor but

  • Osmotic threshold for ADH/VP is much lower than that for thirst

• Vasopressin response occurs first followed by thirst

Possible Secondary Effects of Vasopressin/ ADH

• Central effects on the brain in memory formation and learning

• Anti-fever and pain relief properties

• Social interactions – “fatherly” behaviour, i.e. aggression towards strangers and intruders on one's territory, as well as pair bonding

Diabetes Insipidus

• Disease of PPG or Kidney

  • Related to ADH

• 2 Types

  • Hypothalamic (central)

  • Nephrogenic

Hypothalamic (“Central”) Diabetes Insipidus

• Deficiency in vasopressin secretion 

  • Dehydration – no/ low water reabsorption 

• Caused by head trauma, infections or tumours involving the hypothalamus and prevent the cell bodies from secreting/ transporting hormones from the pituitary stalk

Nephrogenic Diabetes Insidpidus

• Kidney is insensitive to vasopressin effect 

• Caused by: renal disease, mutations in the vasopressin receptor gene or in the gene encoding aquaporin-2

Features of Diaetes Insipidus

• Excessive urine production - up to 16L/day

• If adequate water is available for consumption, the disease is rarely life-threatening, but withholding water can be very dangerous.

Treatment of Hypothalamic/ Central Diabetes Insipidus

• Exogenous vasopressin

• Adequate water supply

Treatment of Nephrogenic Diabetes Insipidus

• Must have adequate water supply at all time

  • Can’t be treated - organs insensitive to ADH effect