Endocrinology Flashcards
Location of adrenal glands
Superior to kidney
Arterial blood supply to adrenal glands
Superior adrenal artery
Middle adrenal artery
Inferior adrenal artery
Origin of
Superior adrenal artery
Middle adrenal artery
Inferior adrenal artery
superior = inferior phrenic artery middle = abdominal aorta inferior = abdominal aorta
Venous drainage of the adrenal glands. Where do they drain into?
Right adrenal vein -> drains directly into inferior vena cava
Left adrenal vein -> drains into left renal vein
Nerve supply of the adrenal glands
Splanchnic nerves
The adrenal gland secretes FIVE main hormones
- Aldosterone
- Cortisol
- Corticosterone
- Dehydroepiandrosterone (DHEA)
- Androstenedione
The cortex is divided into 3 layers (From outside in). What is the name of each layer ?
Zona glomerulosa
Zona fasciculata
Zona reticularis
What does each layer of the adrenal cortex produce?
Zona glomerulosa (mineral corticoids - aldosterone) Zona fasciculata (glucocorticoids i.e. cortisol and small amount of androgens) Zona reticularis (androgens - sex hormones. Small amount of cortisol)
GFR - Makes Good Sex
Which hormones does the adrenal MEDULLA secrete?q
adrenaline and noradrenaline which cause the cortex to secrete further hormones
What do the adrenal medullary hormones respond to? What is their physiological effect as a result?
- They respond to stress
- Dilated pupils, increases glycogenesis, increase lipolysis, increased sweating, increased heart rate and inhibited insulin release
What is a precursor for ALL corticosteroids?
cholesterol
Solubility of corticosteroids
lipid soluble - can pass through biological membranes
What do corticosteroids bind to?
intracellular receptors
Effect of corticosteroids on gene?
Alter gene transcription
How are different steroids classified?
- 21 C = progesterone, corticoids
- 19 C = androgens
- 18 C = oestrogens
- Small structural modifications can substantially alter specificity for steroid receptors
What is the role of mineralcorticoids?
to regulate body electrolytes (minerals)
What is the most predominant mineralcorticoid? What is it important for?
aldosterone
Maintaining salt balance and important for blood pressure as in the RAAS
What triggers the secretion of aldosterone?
the release of renin by juxtaglomerular cells in the afferent arterioles of the kidney
What is the predominant glucocorticoid in humans? What is its role?
- Cortisol
- Facilitates the bodies responses to stress and regulation of the immune system
What are examples of stress/threat which pose a real or perceived threat to homeostasis?
physical trauma, prolonged exposure to cold, prolonged heavy exercise, infection, shock, decreased oxygen supply, sleep deprivation, pain and emotional stress
Stress triggers an increase in the release of …
cortisol
- sympathetic nervous system activity
- release of adrenaline from adrenal medulla
Process of stress detection and subsequent homeostatic response
- Stress is detected and transmitted neuronally to the HYPOTHALAMUS
- This stimulates the secretion of CRH from the hypothalamus
- CRH is carried by the hypothalami-hypopheal portal vessels to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone (ACTH)
- ACTH in turn circulates through the blood and travels to the zona fasciculata, where it binds to the GPCRs. Protein Kinase A (PKA) stimulates the synthesis of cholesterol.
- Cholesterol is converted to pregnenolone in mitochondria and undergoes further processing in the endoplasmic reticulum
- The final conversion to cortisol takes place in the mitochondria
- Once released, CORTISOL enters circulation
% distribution of cortisol in the circulation
- 90% bound to corticosteroid-binding globulin
- 5% bound to albumin
- 5% free - only this is bioavailable
How does cortisol help maintain blood pressure?
It has permissive actions on the reactivity to adrenaline (Vasoconstrictor) and noradrenaline (vasodilator) of smooth muscle scells that surround the lumen of blood vessels
What does cortisol maintain?
Maintain cellular concentrations of enzymes involved in metabolic homeostasis which are expressed mainly in the liver and act to increase hepatic glucose production between meals; thereby preventing glucose concentrations from significantly decreasing below normal.
What doe cortisol inhibit?
Inhibits the production of leukotriene and prostaglandins both of which are involved in inflammations
What does cortisol stabilise?
lysosomal membranes in damaged cells thereby preventing the release of their proteolytic contents
What does cortisol reduce?
capillary permeability in injured areas, thereby reducing fluid leakage to the interstitium
It also suppresses the growth and function of certain key immune cells such as lymphocytes
How does cortisol act as a developmental hormone?
- Responsible for the proper differentiation of numerous tissues and glands including parts of the brain, adrenal medulla, intestines and lungs
- Cortisol is essential for the production of SURFACTANT (reduces the surface tension in the lungs thereby making it easier for the lungs to inflate)
Stress functions of cortisol
- increases organic metabolism (more lipolysis, amino acid generation, and gluconeogenesis)
- This is because when animal is faced with a threat its usually forced to go without eating
- Free amino acids can also help with tissue repair
- Cortisol increases the ability of vascular smooth muscle to contract (vasoconstriction) in response to adrenaline
- Reduces inflammatory response to injury or infection thereby protecting against possible damage as a result of inflammation
- inhibits nonessential functions e.g. reproduction and growth
What can chronic stress result in?
severe decrease in bone density, immune functions and reproductive fertilise due to increased catabolism that is elicited from increased cortisol
Main androgens produced in the zona — are….
Which is the most abundant?
reticularis
- Dehydroepiandrosterone (DHEA)
- Androstenedione
DHEA = most abundant
Do androgens have a stronger effect in males or females?
DHEA and androstenedione have a much less potent effect than testosterone and play less of a role in the adult male yet play a larger role in the adult female, but these weaker androgens can be CONVERTED to testosterone
The production of androgens in the adrenal glands are regulated by the actions of — secreted by the — —
- ACTH
- Anterior pituitary
Adrenaline and noradrenaline are —
catechloamines
Which nervous system is adrenal medulla connected to? It has specialised ganglia that are supplied by — — — with — neurotransmitter
autonomic nervous system
- sympathetic preganglionic neurones
- ACh
What is the proportion of adrenaline vs noradrenaline
- 20% nor
- 80% adrenaline
Normal catechloamine synthesis is dependent on high levels of …
cortisol
Role of catecloamines in “fight or flight” (6)
- gluconeogenesis in the liver and muscle
- lipolysis in adipose tissues
- tachycardia and cardiac contractility
- redistribution of circulating volume
- more adrenaline release - vasoconstrict
- LESS noradrenaline released - vasodilation
Which receptors have a higher affinity for noradrenaline and which have higher affinity for adrenaline
- Alpha - noradrenaline
- Beta - adrenaline
Spinal level thyroid
C5-T1
How many lobes does the thyroid have? What connects them?
2
isthmus
What does the thyroid straddle?
trachea
What does the thyroid lie behind?
sternohyoid and sternothyroid muscles
What does the thyroid wrap around?
cricoid cartilage
superior tracheal rings (2-3 is covered by isthmus)
What does the thyroid lie inferior to?
inferior to thyroid cartilage of the larynx
Arterial supply of the thyroid
superior thyroid artery (1st branch of external carotid artery; supplies the superior and anterior portions)
inferior thyroid artery arises from the subclavian artery; supplies the posterior and inferior portions
Venous drainage of the thyroid
middle + inferior thyroid vein
Thyroid innervation
sympathetic trunk
Hormone release in thyroid is controlled by the …
pituitary gland, NOT sympathetic innervation
When do thyroid glands appear as an epithelial proliferation at the base of the pharynx?
3-4 weeks
When do thyroid glands begin producing thyroxine?
18-20 weeks
What are the two iodine-containing molecules of physiological importance that the thyroid gland produces?
Thyroxine (T4; four iodines)
Triiodothyronine (T3)
T4 is generally converted to T3 by …
In which cells?
deiodinase enzymes
target cells
Is there a higher concentration of T4 or T3 in the blood?
T4, although T3 is considered the major thyroid hormone; T4 can be thought of as a RESEVOIR for T3
Within the thyroid gland are numerous — each composed of an enclosed sphere of — cells surrounding a core containing a protein-rich material called the —
In this material, which protein is there large amounts of?
follicles
follicular
COLLOID
thyroglobulin
Which cells participate in almost all phases of thyroid hormone synthesis and secretion?
follicular epithelial cells
THYROID HORMONE SYNTHESIS
1) circulating iodide is actively co-transported with Na+ ions across the basolateral membranes of the follicular cells (IODIDE TRAPPING) and the Na+ is pumped back out of the cells via the Na+/K+ ATPases.
2) The negatively charged iodide ions diffuse to the apical membrane of the follicular cells and are transported into the colloid.
3) Once inside the colloid, the iodide is oxidised => IODINE which then binds to TYROSINE RESIDUES on the thyroglobulin molecules
4) Tyrosine may bind to 1 or 2 iodine molecules thus either becoming T1 or T2
5) When the thyroid is stimulated to produce thyroid hormone, the T1/2 molecules are cleaved from tyrosine and join to create T3 or T4.
What has to happen for T3 and T4 to be released into the blood?
extensions of the colloid-facing membranes of the follicular cells engulf portions of the colloid by endocytosis
The iodated thyroglobulin is then brought into contact with lysosomes in the cell interior.
PROTEOLYSIS of the thyroglobulin results in the release of T3 and T4 which then are able to diffuse out of the follicular cells into the interstitial fluid -> blood.
What is unique about thyroid glands?
There is sufficient iodinated thyroglobulin stored within follicles of the thyroid to provide thyroid hormone for several weeks even in the absence of dietary iodine - this is unique amongst endocrine glands
All of the actions of the follicular epithelial cells are stimulated by …
TSH (thyroid-stimulating hormone)
What releases TSH?
anterior pituitary
What stimulates TSH?
TRH (thyroid releasing hormone)
What releases TRH?
hypothalamus
What is the basic control mechanism of TSH production?
negative feedback action of T3 and T4 on the anterior pituitary gland and to a lesser extent the hypothalamus
What else does TSH do?
- increases PROTEIN SYNTHESIS in follicular cells
- increases DNA replication & cell division
- increases the amount of rough endoplasmic reticulum and other cellular machinery required by follicular cells for protein synthesis
What will happen if thyroid cells are exposed to greater TSH concentrations than normal?
they will undergo hypertrophy (they will increase in size)
What is the name for an enlarged thyroid gland (any cause)?
Goiter
Where are receptors for thyroid hormone present?
in the nuclei of most cells in the body, unlike receptors for many other hormones
How does T3 act?
by inducing gene transcription and protein synthesis
Overall actions of T3
- Increases metabolic rate (Excess is catabolic resulting in muscle breakdown)
- Important in brain maturation
Metabolic actions of T3
stimulates carbohydrate absorption from the small intestine
increases fatty acid export from adipocytes
produce heat; this is because the previous actions provide energy that helps to maintain the metabolism at a high rate, and the byproduct of metabolic reactions is heat.
Permissive actions of T3
T3 up-regulates beta-adrenergic receptors (For adrenaline) in many tissues e.g. heart and nervous system
Symptoms of over-active thyroid with excess T3
similar to adrenaline due to permissive actions
racing heart, anxiety, nervousness
T3 is required for the normal production of which hormone from the which gland?
growth hormone
anterior pituitary
During fetal life, how does T3 help with the development of the nervous system?
- Formation of axon terminals
- Production of synapses
- Growth of dendrites & dendritic extensions
- Formation of myelin
Other name for pituitary gland?
hypophysis
How is the pituitary gland connected to the hypothalamus?
infundibulum / pituitary stalk
Lobes of pituitary
Anterior (adenohypophysis)
Posterior (neuronhypophysis)
Where does PG sit in the skull?
pituitary fossa
inferior to optic chiasm
Embryological formation of anterior pituitary
A protrusion of ECTODERM from the mouth called RATHKE’S POUCH grows
upwards to form the anterior pituitary (adenohypophysis)
Embryological formation of posterior pituitary
The posterior pituitary (neurohypophysis) is neuronal in origin and is rather a neural extension of the neural components of the hypothalamus - protruding from the developing brain ventrally
Pituitary gland is stimulated to release – hormones by areas of the –
hypophysiotropic hormones
CNS
Secreted hypophysiotrophic hormones reach the – pituitary gland via ———-
What happens next?
anterior pituitary
hypothalamo-hypophyseal portal vessels
They bind specific receptors to stimulate or inhibit release 6 hormones
Generation of AP in these neurons causes theme to secrete hormones via exocytosis
Hypophysiotropic Hormones
Corticotropin-releasing hormone (CRH)
Growth hormone-releasing hormone (GHRH)
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone (GnRH)
Dopamine (DA)
Corticotropin-releasing hormone (CRH)
stimulates release of adrenocorticotropic hormone (ACTH) –> increased cortisol produced in adrenal cortex from zona fasciculata
Growth hormone-releasing hormone (GHRH)
stimulates release of growth hormone (GH) –> growth and protein synthesis
Thyrotropin-releasing hormone (TRH)
stimulates release of thyroid-stimulating hormone (TSH) 🡪 T3 + T4 increase 🡪 increase metabolism
Gonadotropin-releasing hormone (GnRH)
stimulates release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) 🡪 gonads to increase oestrogen, progesterone, testosterone
Dopamine (DA)
inhibits release of prolactin
How many hormone producing type cells does the anterior pituitary have?
5
The anterior pituitary gland has no arterial blood supply? How does it receive blood?
- Receives blood through a portal venous circulation from the hypothalamus -
known as the hypothalamo-hypophyseal portal vessels/veins - The hypothalmo-hypophyseal portal veins offer a local route for blood to be delivered directly from the hypothalamus to the cells of the anterior pituitary
- This local blood system provides a mechanism for hormones of the hypothalamus to directly alter the activity of the cells of the anterior pituitary
gland, bypassing the general circulation and thus efficiently regulating
hormone release from that gland
Nuclei of the hypothalamus secrete hormones which in turn …
control secretion of all the anterior pituitary gland hormones
What is the one exception for the hypophysiotropic hormones which regulate anterior gland function?
dopamine is the only one that is not first in the 3-hormone sequence
3 hormone sequence
1) Hypophysiotropic hormone controls secretion
2) Of anterior pituitary hormone which controls
3) Secretion of hormone from another endocrine gland which acts of target cells
Hormones of the anterior pituitary (6)
Follicle stimulating hormone FSH
Lutenizing hormone LH
Adrenocorticotrophic hormone
Thyroid-stimulating hormone TSH
Prolactin
Growth hormone GH
‘FLATPIG’
Where is each of the anterior pituitary hormones produced?
- Follicle-stimulating hormone (FSH) - produced in gonadotrophs
(basophilic cells - purple/dark blue) - Lutenizing hormone (LH) - produced in gonadotrophs (basophilic
cells - purple/dark blue) - Adrenocorticotropic hormone (ACTH- also known as corticotropin) -
produced in corticotrophs (basophilic cells - purple/dark blue) - Thyroid-stimulating hormone (TSH - also known as thyrotropin) -
produced in thyrotrophs (basophilic cells - purple/dark blue) - Prolactin - prodcued in lactotrophs (acidophilic cells - dark pink/red)
- Growth hormone (GH - also known as somatotropin) - produced in
somatotrophs (acidophilic cells - dark pink/red)
Function of each anterior pituitary hormone
FSH & LH:
• Target the gonads
• Stimulate germ cell development (in females = ovum, in males = sperm)
• Stimulate the release of hormones (in females = estradiol & progesterone, in males = testosterone)
- GH:
• Stimulates growth & protein synthesis - ACTH:
• Stimulates the adrenal cortex to secrete CORTISOL - TSH:
• Stimulates thyroid to secrete T3 & T4 resulting in an increase in
metabolism - Prolactin:
• Stimulates the breasts to produce milk & helps with breast development
Overview of hypophysiotropic hormones and their effect on the anterior pituitary
TRH 🡪 TSH 🡪 increases the release of T3 and T4 🡪 increased metabolism
GnRH 🡪 LH + FSH 🡪 target gonads to increase oestrogen, progesterone and testosterone
GHRH 🡪 GH 🡪 stimulates growth and protein synthesis
Somatostatin 🡪 inhibits GH 🡪 inhibits growth and protein synthesis
CRH 🡪 ACTH 🡪 increase cortisol production in the adrenal cortex
Dopamine 🡪 inhibits prolactin 🡪 inhibits growth and milk production
CRH and ACTH negative feedback
When a stressful stimulus elicits increased secretion of CRH and in turn ACTH and then cortisol, the resulting increased plasma cortisol concentration feeds back to INHIBIT the CRH-secreting neurones of the hypothalamus as well as the ACTH-secreting cells of the anterior pituitary
Why is CRH/ACTH negative feedback important?
excess cortisol has a damaging effect on immune function and metabolic reactions
Which hormones employ long-loop negative feedback?
CRH
FSH
LH
TSH
Why does long loop negative feedback not exist for prolactin, and why does it have short loop negative feedback happen instead?
Long loop negative feedback does not exist for prolactin since this anterior pituitary hormone does not have major control over another endocrine gland - meaning that is does not participate in the three hormone sequence
Short loop negative feedback happens because there is still negative feedback since prolactin acts on the hypothalamus to stimulate the secretion of dopamine which then in turn inhibits the secretion of prolactin.
What does AP gland tumour cause?
pressure on local structures; mainly the optic nerves resulting in bitemporal hemianopia
pressure on the normal pituitary; resulting in excess or inadequate release of pituitary hormones (hypo/hyperpituitarism)
What are the 2 hormones of the posterior pituitary gland?
vasopressin/ADH
oxytocin
The axons of which nuclei pass down the infundibulum to terminate in the posterior pituitary gland? What is their significance?
supraoptic
paraventricular
Enclosed in small vesicles, the hormones move DOWN THE AXONS to accumulate at the axon terminal in the PPG. Various stimuli activate inputs to these neurones, causing action potentials to propagate to the axon terminals and trigger the release of stored hormones via EXOCYTOSIS.
The hormones then enter the capillaries to be carried away by the blood returning to the heart.
ADH
Acts to decrease water secretion by retaining fluid
Acts on smooth muscle cells around blood vessels to cause their constriction resulting in VASOCONSTRICTION; thereby increasing blood pressure that results from blood loss due to an injury
Which nuclei of the hypothalamus secretes ADH
supraoptic primarily
ADH released in response to … (6)
decreased blood volume trauma stress increase PaCO2 Decreased PaO2 increased osmotic pressure of blood
Oxytocin
stimulates the contraction of smooth muscles of the breasts which results in milk ejection during lactation
stimulates the contraction of uterine smooth muscles until the baby is born
promotes the onset of labour
which nuclei synthesis oxytocin
paraventricular nuclei
PPG hormones + time
ADH + oxytocin have a very short half life meaning they are regulated frequently on a minute-to-minute basis
Embryology; where are 2 pancreatic buds formed ?
junction of foregut and midgut the dorsal and ventral p. buds are generated and eventually fuse to form the pancreas
Anatomical position of exocrine pancreas
retroperitoneal
posterior to greater curvature of stomach
head lies near the C-portion of duodenum
98-99% of cells in pancreas
small clusters of glandular epithelial cells: ACINI
Which cells perform exocrine function ?
acinar cells
They manufacture and secrete fluid and digestive enzymes (lipase, trypsin etc): PANCREATIC JUICE.
This is release into gut via the pancreatic ducts
Where do pancreatic ducts enter the small intestine
duodenal papilla (2nd part of duodenum) through the AMPULLA OF VATER
1-2% of pancreatic cells
islets of Langerhans
cells of the islets of Langerhans
delta cells
alpha cells
beta cells
delta cells
secrete somatostatin
alpha cells
secrete glucagon
beta cells
secrete insulin
what do islets of Langerhans release hormones into?
portal vein
peptide hormones secretes by islets of Langerhans
insulin
glucagon
somatostatin
insulin
51 AA polypeptide
reduces glucose output by the liver
increases the storage of fatty acids, and amino acids
stops the breakdown of fat and muscle
glucagon
29 AA PP
mobilises glucose, FA and AAs from their stores
How does insulin regulate carbohydrate metabolism?
suppresses hepative glucose output: decreases glycogenolysis and gluconeogesis
increases glucose uptake into insulin sensitive tissues like muscle and fat
suppresses lipolysis and breakdown of muscle (DECREASE ketogenesis)
How does glucagon regulate carbohydrate metabolism?
increases hepatic glucose output
increases glycogenolysis and gluconeogenesis
reduces peripheral glucose uptake
stimulates peripheral release of gluconeogenic precursors (glycerol and amino acids)
stimulates:
lipolysis
muscle glycogenolysis and breakdown
INCREASED ketogenesis
Insulin production in beta cells of the pancreas
precursor
Proinsulin = precursos
contains Alpha and Beta chains of insuline joined together by a C peptide.
When insulin is being produced, proinsulin is cleaved from its C peptide and then used to make insulin which is then packed into insulin secretory granules.
Insulin secretion by beta cells of the pancreas
Beta cells - GLUT2 glucose transporters.
GLUT2 = low affinity receptor meaning that it only binds when there is a high concentration of glucose.
glucose levels high = GLUT2 receptor activation allowing glucose into the beta cell.
HEXOKINASE: glucose into glucose-6-phosphate
ADP release 🡪 conversion to ATP.
ATP binds to K+ ATP channel and closes potassium channels so they are unable to leave beta cell: DEPOLARISATION.
Opening of voltage-gated calcium channels. Ca2+ ions are able to diffuse into cells.
Ca2+ ions bind to insulin secretory granules resulting in the granule moving to the cell membrane and fusing with it to release its contents via exocytosis.
Effect of insulin on muscle and fat cells
Insulin secreted into the blood will then bind to insulin receptors located on the cell membranes of muscle and fat cells.
This triggers an intracellular signalling casacde resulting in the mobilisation of intracellular GLUT4 vesicles to the cell membrane which fuse to CM.
Increased number of plasma membrane glucose transporters 🡪 greater rate of glucose diffusion INTO cells (facilitated)
This DECREASES BLOOD GLUCOSE LEVELS
What is a short term glucose buffer?
liver glycogen
If blood glucose is high then the liver will convert glucose to glycogen (glycogenesis)
long term - liver will make triglyceride
If blood glucose is low liver will convert glycogen to glucose (glycogenolysis)
long term - liver will make glucose from amino acid/lactate
other than pancreatic islets of Langerhans, where are the other glucose sensors?
medulla
hypothalamus
carotid bodies
What are incretins?
They are secreted by endothelial cells in the GI tract in response to eating - amplifies the insulin response to glucose.
What are the major incretins?
glucagon-like peptide 1 (GLP-1)
Glucose-dependent insulinotropic peptide (GIP)
2 main mechanisms for regulating pospranidal (post-meal) glucose levels?
- Rising plasma glucose stimulates pancreatic beta cells to secrete insulin
- Plasma glucose inhibits glucagon secretion by pancreatic alpha cells
Parathyroid glands - anatomy
2 superior + 2 inferior parathyroid glands
Located on posterior aspect of the lateral lobes of the thyroid
Parathyroid blood supply and drainage
supplied by inferior thyroid artery (From subclavian artery)
drains into thyroid plexus
parathyroid innervation
sympathetic trunk
- only vasomotor innervation
- secretions are controlled hormonally
Function of parathyroid gland
regulate calcium and phosphate levels
secrete parathyroid hormone in response to LOW calcium or HIGH phosphate
Parathyroid hormone actions (5)
Increases calcium reabsorption in renal distal tubule
Increases intestinal calcium absorption (via activation of vitamin D) – duodenum and jejunum
Increases calcium release from bone (stimulated osteoclasts activity)
Decreases phosphate reabsorption
Binds to GPCRs
PTH transcription is inhibited by
1,25D3 (calcitrol)
Primary Hyperparathyroidism
Parathyroid tumour
Causes hypercalcaemia and low serum phosphate
Loss of negative feedback from hypercalcaemia
Treatment is surgery
Secondary Hyperparathyroidism
Renal disease
Increased phosphate and decreased activation of vitamin D
Treat with phosphate binders or vitamin D analogues
Tertiary Hyperparathyroidism
Long-standing secondary HPT leads to irreversible parathyroid hyperplasia
Usually seen when renal disease is corrected, i.e. transplantation
Treatment is surgery
