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Pit hormones are tropic hormones
Releasing hormones (from the hypothalamus- stimulate the anterior pituitary to release hormones):
Growth hormone releasing hormone (GHRH) - GH
Prolactin releasing hormone (PRH)- Prolactin
Corticotrophin releasing hormone (CRH) - ACTH
Thyrotropin releasing hormone (TRH) - TSH
Gonadotrophin releasing hormone (GnRH)- LH + FSH
Inhibitory hormones (from the hypothalamus- inhibit the release of anterior pituitary hormones)
Growth hormone release inhibitor somatostatin (SS) - GH
Dopamine (DA)/Prolactin inhibitory factor (PIF)- GH/Prolactin Growth hormone/ Somatotrophin (GH)- protein (191)
Stimulates the release of insulin-like growth factors from the liver
Prolactin - protein (198)Prepares the breast for lactation
Suppresses ovulation
Adrenocorticotrophic Hormone (ACTH) - polypeptide (39)
Stimulates the release of adrenal cortical hormones
Thyroid Stimulating Hormone (TSH) - glycoprotein (201)
Stimualtes the release of thyroid hormones
Follicle Stimulating Hormone (FSH)- glycoprotein (115)
Stimulates gonadal function
Leutenizing hormone (LH) - (glycoprotein 115)
Stimulates gonadal function
Most pituitary hormones have direct effects on tissues but also stimulate the release of other circulating hormones that feedback to the hypothalamus and pituitary
TSH acts on the thyroid stimulating it to release thyroxine
LH and FSH act on the gonads stimulating the release of oestrogen, progesterone and androgens
GH stimulates the liver to release IGF-1
ACTH stimulates the adrenal glands to release cortisol The hypothalamus also secretes hormones which are then stored in and released from the posterior pituitary
The nuclei of supraoptic and paraventicular cells are found in the hypothalamus while the nerve endings are found in the posterior pituitary
The posterior pituitary releases:
Oxytocin
This important for the reflex of milk secretion (not production and storage, prolactin’s role)
Vasopressin (antidiuretic hormone - ADH)
Important for the reabsorption of water by the kidneys throughV2 receptors (without it, diabetes insipidus arises)
Also causes vasoconstriction via receptors on vascular smooth muscle and kidneys through V1 receptors
Both are short peptides (9 amino acids) to be stored in nerves Anterior Posterior Causes This is usually panhypopituitarism
It rarely affects individual hormones
There are many causes
Iatrogenic
Surgery
Radiation
Trauma- sudden haemorrhage into gland
RTA
Fractured skull
Tumours extending into sella
Pituitary tumour
Secondary metastatic leasion (lung, breast)
Local brain tumour (astrocytoma, meningioma, glioma)
Granulomatous Disease
Sarcoidosis
TB
Histiocytosis
Polyarteritis
Hypothalamic Infectious Diseases
Syphilis
Meningitis
Autoimmune
Sheehan's Syndrome Hypopituitarism Pituitary Adenoma Pituitary disorders can present as a result of:
Too much hormone
Too little hormone
Overgrowth of the gland
There may be all three- if a growth secretes and excess of one hormone while simultaneously pressing against areas of the pituitary which produce other hormones
Most pituitary tumours are benign- they are rarely carcinomas and usually adenomas
Problems resulting from non-functioning pituitary adenoma:
Compression on optic chiasm- results in bilateral hemionopia
Compression on cranial nerves (especially 3,4,6)
Hypoadrenalism
Hypothyroidism
Hypogonadism
Diabetes Insipidus
GH Deficiency Symptoms Menstrual irregularity (F)Impotence/InfertilityGynaecomastia (M)Abdominal obesityLoss of facial hair (M)Loss of axillary and pubic hair (M and F)Dry skin and hairHypothyroid faceGrowth retardation in childrenWeight loss Investigations Levels Free T4 (low)
TSH (low- can also be low in destroyed pituitary, due to negative feedback)
Estradiol (low)
Testosterone (low)
LH (low)
FSH (low)
GH (low)
IGF-1 (low)
Prolactin (low) Dynamic If it appears to be too much hormone, do a test to suppress it
If it appears to be too little hormone, do a test to stimulate it
SynACTHen test
Synthetic ACTH given
Cortisol levels measured at 0, 30 and 60 mins
If cortisol levels increase, pituitary issue, else, adrenal issue
Insulin Stress Test/Prolonged Glucagon Test
Insulin is given
Cortisol + GH levels measured every 30mins for 2-3 hours
Normal cortisol >550
Normal GH > 7ug
If GH and cortisol become normal, implies pituitary issue Treatment T4:
100-150mcg/day
Hydrocortisone:
10-25mg/day
GH:
SubCut GH nightly
Sex steroids:
Oest/Prog pill (F)
Testosterone (M) Testosterone IM injection every 3-4 weeks
Skin patches (andropatch)
Skin gel (testogel)
Prolonged IM injection 10-14 weeks (nebido)
Oral tablets (restandol) - as it is a peptide, not usually given orally
Risks:
Prostate enlargement (NOT cancer)- monitor size
Polycythaemia- monitor FBC
Hepatitis (if oral)- monitor LFTs Growth Hormone Improves quality of life
Decreases abdominal fat
Increases muscle mass, strength, exercise capacity and stamina
Improves caridac function
Decreases cholesterol
Increases LDL
Increases bone density
Given SubCut daily Hyperpituitarism Derived from cells of anterior pituitary
Relatively common (10% intra-cranial tumours)
Sporadic or associated with MEN1
Prolactin (20-30%)
Most common
Symptoms: Infertility, Lack of libido, Amenorrhoea (25%)
ACTH (10-15%)
Leads to Cushing’s disease
Usually a micro-adenoma
Bilateral adrenocortical hyperplasia occurs
FSH/LH (10-15%)
Non functioning, large gonads
GH (5%)
Second most common
Stimulates growth of bone, cartilage and connective tissue
Can produce more than one (even at sub-clinical levels)
Can be hypo / non-functional
Large adenomas
Visual field defects
Can cause pressure atrophy of surrounding normal tissue
Infarction can lead to panhypopituitarism
Carcinoma Hypofunction
Diabetes Insipidus
Lack of ADH secretion
Can lead to life threatening dehydration
Water Deprivation Test
Water not taken at length
Serum and urine osmolarities measured for 8h Again 4h after giving IM DDAVP
If urine/serum osmolarity >2, it is normal, else,
Give ADH as desmospray or tablets
Hyperfunction
Syndrome of Inappropriate ADH secretion (SIADH)
Ectopic secretion of ADH by tumours
Primary disorder in the pituitary Blood Glucose + Insulin Biochemistry Disease Structure Pancreas has alpha, beta and delta cells
Exocrine- involves secretion of pancreatic digestive enzymes into SI
Endocrine- secretion of hormones into the blood stream
Exocrine cells surround Islets of Langerhans which have 3 cell types
Beta cells- secrete insulin (51aa), in the core
Alpha cells- secrete glucagon (29aa), around the periphery
Delta cells- secrete somatostatin, around the perphery
PP cells- secrete pancreatic polypeptide
Islets have capillaries within- supply core then periphery
Beta cells bathe alpha and delta cells with insulin (paracrine effect)
Parasympathetic and sympathetic innervation
Peptide Structure
Synthesized in the RER
Synthesized into a preprohormone- preproinsulin
Cleaved to form insulin
Preproinsulin contains two polypeptide chains linked by disulfide bonds (between cysteines)
One chain is lost to form proinsulin and a signaling chain
A second chain is lost to form insulin and C peptide
C peptide is a byproduct of the second cleavage- has no physiological function
Amino Acid Sequence
Similar in all species
Differences do not affect the activity if transferred between species
However, from another species, insulin is antigenic
It will induce antibody formation against the insulin Release Glucose enters beta cells through the GLUT2 transporter and is phosphorylated by glucokinase
Increased extracellular glucose leads to increased uptake/transport, increasing intracellular levels
There is more phosphorylated glucose and more ATP
Glucokinase is a glucose sensor- it is an enzyme used for glucose phosphorylation
It has a Km (affinity for the substrate - high Km means low affinity) which lies in the physiological range of concentrations
A small change in glucose concentrations leads to a dramatic change in glucokinase activity (i.e.

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phosphorylation)
This is not true for hexokinase, which is found in RBCs- it is virtually always at maximum capacity
Glucose then undergoes glycolysis and enters the TCA cycle to form ATP
Increased metabolism of glucose (at increased conc) leads to an increase in the intracellular ATP
ATP inhibits the ATP-sensitive K+ channel, KATP
This channel moves potassium from the inside to the outside of the cell
It is used to maintain the membrane potential
With increased glucose concentration there is increased inhibition of KATP
KATP stop pumping potassium from the inside to the outside
There is then depolarisation of the membrane
This voltage change affects the voltage gated calcium channel activity
Voltage gated calcium channels open allowing in calcium
Increased internal calcium concentration causes the mobilisation of secretory vesicles (containing insulin) within the cell
The secretory vesicles fuse with the cell membrane and insulin is released extra-cellularly Timing The insulin release is biphasic
Not just one burst
1st peak due to the secretion of insulin
This release is somewhat sustained
There is then a second phase with a second peak
There are 2 phases because there are 2 different types of vesicle
5% of insulin granules are immediately available for release in the RRP- readily releasable pool (already partly fused)
Others need to fuse with the membrane and undergo preparatory actions to be mobilised and ready for release Modulation GLP 1 helps modulate insulin secretion
GLP-1 is Glucagon-like peptide 1
It is released by the GI tract in response to food intake orally
It stimulates insulin secretion in healthy subjects
Oral glucose therefore leads to higher insulin secretion than intravenous injection
GLP-1 binding to its receptor leads to the activation of adenylate kinase and an increase in cAMP
This stimulates intermediates resulting in increased insulin- when acting in combination with other signals
PKA and Epac2 are activated
This has numerous effects on ion channel activity, calcium and exocytosis of insulin granules Inhibition KATP channel structure:
KATP consists of 2 protein subunit types- there are 4 of each
Inward rectifier subunit- Kir6.1
Sulphonylurea receptor-regulatory subunit- SUR1
Both are needed to form a functional channel
Channel has an octomeric structure
4 SUR1 receptors around 4 Kir6.1 proteins
The peptides transverse the membrane several times so some domains are inside while others are outside
Two of the inside domains on SUR1 are nucleotide binding domains
Kir moves potassium out while SUR1 regulates this movement
Intracellular ATP binds to the nucleotide binding domain on the inside of the cell on the SUR1 sub-unit
It inhibits the binding of potassium, stopping the pumping
Magnesium salt bound nucleotides (Mg2+ ATP and ADP) activate KATP by binding to the SUR1 sub-unit
Therefore ATP can inhibit OR activate pumping of potassium
KATP is directly inhibited by the sulphonylurea class of drugs (tolbutamide and glibenclamide)- they inhibit the SUR regulator by binding extracellularly , causing depolarisation and thus more insulin secretion
KATP is directly stimulated by diazoxide, which binds extracellularly to SUR1 and thus inhibits insulin secretion and increases potassium binding and transport Signalling Insulin sensitive tissues include the liver and skeletal muscle
It is a peptide and so cannot cross the plasma membrane- needs a receptor
The receptor type is a tyrosine kinase
It is dimeric
It has two extracellular alpha subunits (hormone binding domains) and two transmembrane beta subunits (ATP binding and tyrosine kinase domains)
The components are linked by disulphide bonds
The binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves
This activates catalytic activity of the receptor
Receptors are docking centres for other enzymes- recruit and activate further signalling molecules (including the RAS/MAPK pathway and gene expression)
There are several intracellular insulin receptor substrates which are phosphorylated when insulin enters the receptor
The substrate activates the PI-3K pathway
PI-3K activates protein kinase B
Protein kinase B activates glycogen synthase kinase 3 and protein phosphotase 1
Glycogen synthesis is activated
Protein kinase B also causes the movement of GLUT4 transporters from intracellular vesicles to the cell surface
This lowers blood glucose, as glucose moves into the cell
When blood glucose returns to normal transporters are endocytosed Effects Amino acid uptake in muscle
DNA synthesis
Growth responses
Glucose uptake in muscle and adipose tissue
Protein synthesis
Lipogenesis in adipose tissue and the liver
Glycogen synthesis in liver and muscle
Gene expression
Lipolysis
Gluconeogenesis in the liver Unavailability Ketone bodies are formed in liver mitochondria
They are derived from acetyl CoA from beta oxidation
They diffuse into the blood stream and into peripheral tissues
They are important for the energy metabolism of the heart and renal cortex- they are converted back to acetyl CoA which re-enters the TCA cycle
Fatty acid oxidation produces acetyl CoA which when combined with oxaloacetate can produce citrate
If oxaloacetate is consumed for gluconeogenesis, fatty acids are oxifdised to produce acetyl CoA, the excess of which, since unable to combine with oxaloacetate, forms ketone bodies
When ketone bodies accumulate they can lead to acidosis
This can cause coma and death
Ketoacidosis is associated with type 1 diabetes
There are high concentrations of insulin in type 2 and this inhibits hormone sensitive lipase so stored triglycerides are not broken down Sensing AMP (adenosine monophosphate) activated protein kinase
Maintains energy balance
Activated by metabolic stress
Inhibition of ATP production
Acceleration of ATP consumption
Activates catabolic pathways which generate ATP
Inhibits anabolic pathways which consume ATP
AMP activates the phosphorylated enzyme (kinase) allosterically
It promotes phosphorylation by upstream kinases
It inhibits dephosphorylation by protein phosphotases
It antagonises the binding of ATP
Why AMP?
Hydrolysis of ATP leads to ADP formation
However it is the AMP:ADP ratio that is important
This is because 2ADP

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Angiotensinogen -> AI->AII (using ACE) leading to vasoconstriction and aldosterone production
Zona Fasciculata –
Glucocorticoids
Cortisol
Regulated by ACTH (and thus CRH)
Zona Reticularis –
Sex Steroids + Glucocorticoids
DHEA (precursor to testosterone)
Regulated by ACTH (and thus CRH)
Medulla:
Distinct from cortex
Innervated by pre-synaptic fibres from the sympathetic splanchnic nerves
Neuroendocrine (chromaffin) cells- secrete catecholamines (noradrenaline, adrenaline)- these reduce salts to chromium, creating a brown colour
Tyrosine -> L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline Cortisol Function Corticosteroids bind to intracellular receptors which form a receptor ligand complex
This complex binds to DNA affecting transcription
There are 6 classes of steroid receptor:
Glucocorticoid
Mineralocorticoid
Progestin
Oestrogen
Androgen
Vitamin D
Clinical application:
Suppress inflammation
Suppress immune system
Replacement treatment
Treatment for:
Allergic disease- asthma, anaphylaxis
Inflammatory disease- RA, UC, Crohns
Malignant disease Actions of cortisol:
CNS:
Mood
Euphoria
Psychosis
Decreased Libido
Bone/Connective Tissue:
Accellerates osteoporosis
Decreased serum calcium
Decreased collagen formation
Decreased wound healing
Immune:
Decreased capillary dilation and permeability
Decreased leukocyte migration
Decreased macrophage activity
Decreased inflammatory cytokine production
Metabolism:
Increased carbohydrate metabolism
Increased blood sugar
Increased lipid metabolism
Increased lipolysisI
ncreased central redistribution
Increased protein metabolism
Increased proteolysis Hypercortisolism Causes Causes:
Adrenal Hyperplasia
These may be diffuse or nodular
Diffuse are more frequently ACTH driven
Nodular are usually ACTH independent
Can be bilateral enlargement
Enlargement up to 30g
Hypersecretion
Aetiology:
ACTH Dependent (cause hyperplasia)
Pituitary (80%+) (Cushing's DISEASE)
Ectopic
Thymus
Lung (can occur in para-neoplastic syndrome with small cell cancer)
Pancreas
ACTH Independent
Malignancy of adrenal gland:
Adenoma
Carcinoma
Pseudo
Alcohol and depression
Steroid medication (including inhalers)
Non-lesional gland atrophy (hyperplasia) Congential Adrenal Hyperplasia Rare group of autosomal recessive disorders
Deficiency or lack of enzyme needed for steroid biosynthesis
Most common is 21 alpha hydroxylase deficiency (also 11B and 17a)
Aldoterone and cortisol cannot be formed from cholesterol
Altered biosynthesis leads to increased androgen (progesterone, testosterone) production
There is masculinsation and precocious puberty as a result of excess androgen
Reduced cortisol stimulates ACTH release and cortical hyperplasia
Presentation:
Classical:
Males:
Adrenal insufficiency (aroudn 2-3 weeks)
Poor weight gain
Biochemical pattern (see Addison’s)
Females:
Ambiguous genitalia
Non-classical:
Hirsutism
Acne
Oligomenorrhoea
Precocious puberty
Infertility or sub-fertility
Treatment:
Paediatrics:
Glucocorticoid replacement
Mineralocorticoid replacement if needed
Surgical correction
Help achieve maximal growth potential
Adult physician:
Control androgen excess
Restore fertility
Avoid steroid over-replacement Tumours These occur mainly in adults, can occur in younger patients with Li-Fraumeni syndrome
The numbers in males and females are equalsIt can present as a result of:
An incidental finding
Hormonal effects
Mass lesion
Distinguishing malignant and benign is difficult, metastasis is the only definite criteria
Adenoma
These are well circumscribed and encapsulate, usually small 2-3cm
They are yellow-brown
The cells resemble adrenocortical cells
The cells are well differentiated (occasionally function), with small nuclei and rare mitoses
Carcinoma
This is rare (5y survival of 20-35%)
More likely functional, virilising tumours that are usually malignant
The can closely resemble adenoma
Spread:
Local invasion: retroperitoneum, kidney
Metastases: usually vascular
Peritoneum and pleura
Regional lymph nodes
Features:
Large size (>50g, usually >20)
Frequent atypical mitoses
Lack of clear cells
Capsular or vascular invasion Symptoms Facial plethora (facial flushing)
Striae (abdominal especially)
Thin skin
Proximal myopathy
Frontal balding in women
Conjunctival oedema
Osteoporosis (this is less likely in those who are overweight, therefore if someone is obese and has osteoporosis, Cushing’s is likely)
Abdominal obesity (lemon on matchstick appearance)
Benging intercranial hypertension
Moon face
Easy bruising
Poor wound healing
Thin arms and legs
Buffalo hump
Emotional liabitlity- euphoria, depression
Tendency to hyperglycaemia
Negative nitrogen balance
Increased appetite
Increased susceptibility to infection Diagnosis Screening Tests
Overnight 1mg dexamethasone suppression test (normal adrenal should suppress cortisol when steroid is given, hypothalamus detects and suppresses CRH, pituitary suppresses ACTH)
Cortisol

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