Endocrine Flashcards
Describe the connections between the hypothalamus and anterior/posterior pituitary gland
There are neural connections between the hypothalamus and posterior pituitary
There are vascular connections between the hypothalamus and anterior pituitary
Where are the cell bodies of the nerves with endings in the posterior pituitary?
Supraoptic and paraventricular nuclei - neurons pass to the posterior pituitary via the hypothalamohypohysial tract
What vessels form the primary plexus?
Primary plexus - network of fenestrated capillaries on the ventral surface of the hypothalamus
Formed by arterial twigs from the carotid arteries and circle of Willis
What is the median eminence?
The portion of the ventral hypothalamus from which the portal vessels arise
This region is OUTSIDE the BBB
What are the principal functions of the hypothalamus?
- Temperature regulation
- Neuroendocrine control of:
- Catecholamines
- Vasopressin
- Oxytocin
- TSH via TRH
- ACTH via CRH
- FSH and LH via GnRH
- Prolactin via PRH
- GH via somatostatin and GRH
- “Appetite” behaviour
- Defensive reactions
- Control of body rhythms
What 6 hormones are secreted by the anterior pituitary?
Adrenocorticotrophic hormone (ACTH)
Thyroid stimulating hormone (TSH)
Growth hormone (GH)
Follicle stimulating hormone (FSH)
Luteinizing hormone (LH)
Prolactin (PRL)
What are the hypophysiotropic hormones?
Hormones secreted into the portal hypophysial vessels from the hypothalamus to the pituitary (secreted by the median eminence)
Corticotropin-releasing hormone (CRH)
Thyroid releasing hormone (TRH)
Growth hormone releasing hormone (GRH)
Growth hormone inhibiting hormone (GIH/somatostatin)
Prolactin inhibiting hormone (PIH)
Gonadotropin releasing hormone (GNRH)
Where are the cell bodies of the neurons that secrete the hypophysiotropic hormones?
GNRH - Medial preoptic area
Somatostatin - Periventricular nuclei
TRH - Periventricular nuclei
CRH - Periventriuclar nuclei
GRH - Arcuate nuclei
Describe the anatomy of the anterior pituitary
Arises embryolgically as an invagination of the pharynx (Rathke pouch)
Contains endocrine cells that store its characteristic hormones
What are the 5 types of secretory cells identified in the anterior pituitary?
Somatrotropes (50%)
Lactotropes (10-30%)
Corticotropes (10%)
Thyrotropes (5%)
Gonadotropes (20%)
What percentage of the ciruclating pool of growth hormone is in the bound form?
50% - providing a resevoir of hormone to compensate for the wide fluctuations that occur in secretion
At what age do you have the highest circulating levels of growth hormone?
Adolescents > Children > Adults
What are the regulators of GH secretion?
GHRH and somatostatin secreted by the hypothalamus
Ghrelin - mainly synthesised and secreted in the stomach, also produced in the hypothalamus
GH acts on the hypothalamus to antagonise GHRH release and stimulate somatostatin release
What factors increase GH secretion?
- Hypoglycaemia
- 2-Deoxyglucose
- Exercise
- Fasting
- Increase in amino acids
- Protein meal
- Infusion of arginine
- Glucagon
- Lysine vasopressin
- Going to sleep
- L-Dopa and alpha-adrenergic agonists that penetrate the brain
- Apomorphine and other dopamine receptor agonists
- Oestrogens and androgens
- Stressful stimuli
- Pyrogen
3 BROAD GROUPS: 1-Hypolgycaemia/fasting- threatened decrease in substrate for energy production. 2- Increase in aminoacids in the plasma 3-Stressful stimuli
What stimuli decrease GH secretion?
REM sleep
Glucose
Cortisol
FFA
Medroxyprogesterone
GH and IGF-1
What important signalling cascades are activated by Growth hormone?
- PLC/PIP2/DAG
- JAK2-STAT pathway
- JAK2 is a cytoplasmic tyrosine kinase
- STATs are a family of cytoplasmic transcription that upon phosphorylation by JAK kinases migrate to the nucleus where they activate various genes
What are the effects of growth hormone on protein/electrolytes?
Rise in plasma phosphorus
Fall in BUN and amino acid levels
Increased GI absorption of Ca2+
Reduced Na+ and K+ excretion
Increased excretion of amino acid 4-hydroxyproline
Increase in lean body mass and decrease in body fat
What are the effects of growth hormone on carbohydrate and fat metabolism?
Many forms are diabetogenic
- Increase hepatic glucose output
- Exert anti-insulin effect in muscle
- Ketogenic
- Increases circulating FFA levels
Increases ability of pancreas to respond to insulinogenic stimuli
Describe the role of somatomedins (IGF) in growth
- Insulin like growth factors (IGF) are polypeptide growth factors secreted by the liver and other tissues
- Circulating somatomedins include IGF-1 and IGF-2
- Both are tightly bound to proteins in plasma
- IGF-1 receptor is very similar to insulin receptor. Secretion stimulated by GH.
- IGF-2 receptor has distinct structure. Largely independant of GH. Role in growth of fetus before birth.
What are the actions of GH and IGF?
- Na+ retention
- Decreased insulin sensitivity
- Lipolysis
- Protein synthesis
- Epiphysial growth
- IGF 1 - insulin like activity, antilipolytic activity
What are the effects of pituitary insufficiency?
Adrenal cortex atrophies > secretion of adrenal glucocorticoids and sex hormones falls to low levels
Stress induced increases in aldosterone secretion are absent but basal aldosterone secretion and increases induced by salt depletion are normal > Salt loss and hypovolaemic shock do not develop but inability to increase glucocorticoid secretion makes patients sensitive to stress
Growth is inhibited
Thyroid function is depressed to low levels > cold intolerance
Gonadal atrophy
Secondary sexual characteristics disappear
Tendency to become hypoglycaemic -> increased hypoglycaemic effect of insulin
Transient polyuria - ACTH, TSH and GH all have a “diuretic” effect which balances the ADH secretion by the post. pituitary. Selective destruction of the supraoptic post. pituitary causes diabetes insipidus
What are the causes of pituitary insufficiency?
Tumour
Suprasellar cysts - remnants of Rathke pouch
Sheehan syndrome - infarction of the pituitary secondary to post-partum haemorrhage
Name the different hormones secreted by the adrenal cortex and adrenal medulla
Outer adrenal cortex - glucocorticoids eg cortisol, mineralocorticoids eg aldosterone
Inner adrenal medulla - catecholamines
Describe the morphology of the adrenal medulla
- 28% of the mass of the adrenal gland
- Interlacing cords of densely innervated granule-containing cells that abut on venous sinouses
- 2 distinguishable cell types:
- Epinephrine secreting cells (90%) - larger, less dense granules
- Norepinephrine secreting cells (10%) - smaller, very dense granules
Paraganglia - cells resembling adrenal medullary cells are found near the thoracic and abdominal sympathetic ganglia
Describe the morphology of the adrenal cortex
Three zones:
- Outer zona glomerulosa (15% of adrenal mass) –> aldosterone secretion, formation of new cortical cells
- Zona fasciculata (50% of adrenal mass) –> cortisol and androgens
- Zona reticularis (7% of adrenal mass) –> androgens and cortisol
What is the vascular supply to the adrenals?
Arterial - Small branches of the phrenic and renal arteries and the aorta
Blood flows from a plexus in the capsule through the cortex to the sinusoids of the medulla.
Veinous- From the medulla into a central adrenal vein
Describe the synthesis of catecholamines in the adrenal medulla
Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine
Epinephrine is formed by methylation of norepinephrine
Phenylethanolamine-N-methyltransferase (PNMT) is the enzyme that catalyses the formation of epinephrine from norepinephrine
PNMT is induced by glucocorticoids > If the glucocorticoid concentration falls (eg after hypohysectomy) epinephrine synthesis falls
Most of the catecholamine output in the adrenal vein is epinephrine
Norepinephrine is also secreted by noradrenergic nerve endings
What are the effects of epinephrine and norepinephrine?
- Glycogenolysis in liver and skeletal muscle
- Mobilisation of FFA
- Increased plasma lactate
- Stimulation of the metabolic rate
- Increase force and rate of contraction of the heart (via B1 receptors)
-
NE –> acts via A1 receptors causing vasoconstriction
- HTN stimulates aortic baroreceptors producing reflex bradycardia that overrides direct cardioaccelatory effect of NE
-
E –> acts via B2 receptors causing vasodilation in liver and skeletal muscle –> TPR drops
- Widening pulse pressure but insufficient baroreceptor stimulation to cause bradycardia > Cardiac rate and output increase
- Increased alertness
- Initial rise in plasma K+, prolonged fall in plasma K+ due to uptake by skeletal muscle
What is the threshold for the cardiovascular and metabolic effects of NE and E?
NE = 1500 pg/mL (5 times the resting value)
E = 50 pg/mL (2 times the resting value)
What are the observed effects of dopamine?
- Renal vasodilation + mesenteric vasodilation
- Vasoconstriction elsewhere (increased NE release)
- Positive inotropic effect on heart (B1 receptors)
- Increased systolic pressure and no change on diastolic pressure
- Natriuresis (?inhibits Na/K ATPase)
Other than catecholamines, what other substances are secreted by the adrenal medulla?
ATP
Chromogranin A
Opioid peptides (preproenkephalin role unknown)
Adrenomedullin (vasoDepressor polypeptide)
Describe the action of ACTH
Binds to high affinity receptors on plasma membrane of adrenocortical cells
Activates adenylyl cyclase via Gs
Increased formation of pregnenelone and its derivatives
Over longer periods - increases the synthesis of the P450s involved in the synthesis of glucocorticoids
Describe the action of angiotensin 2
Binds to AT1 receptors in the zona glomerulosa that act via a G protein to activate phospholipase C > increased PKC > Conversion of cholestrol to pregnenolone + increased action of aldosterone synthase resulting in increased secretion of aldosterone
How is cortisol found in the circulation?
Bound to an alpha globulin called transcortin or corticosteroid binding globulin (CBG)
Minor degree of binding to albumin
Corticosterone is bound to a lesser degree and therefore has a shorter half life
Bound steroids are physiologically inactive
The bound cortisol functions as a resevoir
Describe the metabolism and excretion of glucocorticoids
Metabolised in the liver
Reduced to dihydrocortisol and then to tetrahydrocortisol which is conjugated to glucoronic acid (same glucoronyl transferase catalyst as bilirubin glucoronides)
Enzyme 11B hydroxysteroid dehydrogenase:
Type 1 ctalyses conversion of cortisol to cortisone+reverse reaction and forms cortisol from corticosterone
Type 2 catalyses one way conversion of cortisol to cortisone
How is aldosterone excreted?
Converted in the liver to the tetrahydroglucoronide derivative
This glucoronide is converted to free aldosterone by hydrolysis at pH 1 and is often referred to as the acid-labile conjugate
Less than 1% of the secreted aldosterone appears in the urine as the free from
What is the mechanism of action of glucocorticoids?
Bind to glucocorticoid receptors –> Steroid-receptor complexes act as transcription factros –> mRNA –> synthesis of enzymes that alter cell function
What are the physiologic effects of glucocorticoids ?
- Effects on intermedullary metabolism
- protein catabolism, increased hepatic glycogenesis and gluconeogenesis, glucose-6-phosphatase activity increases > plasma glucose rises
- Permissive action
- Must be present for certain metabolic reactions to occur eg glucagon
- Inhibit ACTH secretion
- Inhibit ACTH secretion
- Necessary for vascular reactivity
- Necessary for CNS function
- Necessary for excretion of water loads
- Effects on blood cells and lymphatic organs
- Decrease number of circulating eosinophils, basophils
- Increase neutrophils, platelets, RBCs in circulation
- Inhibit the inflammatory response
- Suppress manifestations of allergic disease that are due to the release of histamine
Describe the regulation of glucocorticoid secretion
Release is dependant on ACTH from the ant. pituitary
Normal basal ACTH release maintains serum levels
Increased ACTH in response to stress occurs
What are the stimulators of ACTH secretion
Pain
Emotion
Circadian rhythm
Nucleus of the tractus solitarius (chemoreceptor and baroreceptors)
Free glucocroticoids inhibit ACTH secretion at the hypothalamic and pituitary level
Describe the MOA of aldosterone
Binds to cytoplasmic receptor > receptor-hormone complex > moves to nucleus > transcription of mRNA > production of protein that alter cell function
Rapid effect: Increased activity of epithelial Na+ channels ENaCs by increasing the insertion of these into the cell membrane from a cytoplasmic pool
Slower effect: Increased synthesis of ENaCs
What are the actions of aldosterone?
Increased reabsorption of Na+ from urine, sweat, saliva, contents of colon
Decreased reabsorption of K+ from the urine
Primary regulators of aldosterone secretion
Ciruclating ACTH level
The RAA system
Increased K+ concentration increases release
What stimuli increase aldosterone secretion?
Stimuli that increase glucocorticoid secretion
- Surgery
- Anxiety
- Trauma
- Haemorrhage
Stimuli that do not affect glucocorticoid secretion
- High K+ intake, low Na intake
- Concentration of IVC in thorax
- Standing
- Secondary hyperaldosteronism
What are the relative potencies of corticosteroids compared with cortisol?
Dexamethasone has 0 mineralocorticoid activity but has the most glucocorticoid activity
What are the functions of the thyroid gland?
Stimulates O2 consumption of most cells in the body
Helps regulate lipid and carbohydrate metabolism
Necessary for growth and maturation
Regulates calcium metabolism - seretes calcitonin
Describe how iodine is used by the body
Minimum daily iodine intake 150microgram
Usual daily take 500microgram
About 120microgram/day enters the thyroid
80 microgram/day (2/3) secreted in the form of T3 and T4
40micogram/day (1/3) diffuses back into ECF
20microgram/day lost in stool
20% dietary I- enters the thyroid, 80% excreted in urine
Describe the process of iodide transport across throcytes
Na/I symporter (NIS) in the basolateral membrane of thyrocytes pumps 2 Na and 1 I into the cell with each cycle
- This is secondary active transport - energy is provided by active transport of Na+ out of thyroid cells by the Na/K ATPase
- TSH induces NIS expression and retention of NIS in the basolateral membrane
What are the key steps in thyroid hormone synthesis?
Iodide oxidised to iodine at interface between thyrocyte and colloid.
Iodine is bound to thyroglobulin in the colloid.
The process is mediated by membrane bound thyroid peroxidase
- Monoiodotyrosine is produced (MIT)
- MIT is iodinated to diiodotyrosine (DIT)
- 2 DIT molecules undergo oxidateive condensation to form T4 (removal of alalnine)
- T3 is formed by condensation of DIT with MIT
Thyroglobulin is synthesised in the thyrocytes and secreted into the colloid by exocytosis of granules
Thyroid hormones remain part of the thyroglobulin molecules until they are secreted - colloid is then ingested by the thyroid cells, peptide bonds hydrolysed and free T4 and T3 are discharged into capillaries
What are the 4 functions of thyroid cells?
Collect and transport iodine
Synthesis of thyroglobulin and secretion into colloid
Fix iodine to the thyroglobulin to generate thyroid hormones
Removal of thyroid hormones from thyroglobulin and secretion into circulation
