BIOM 3200 - Endocrine System

What does this concept refer to: "our internal environment remains remarkably consistent despite changes in the external milieu"?

- Homeostasis

What is the general description of homeostasis?

- The relative stability of the internal environment even though we are always internally / externally changing (we are adapting to try and go back to normal)

What type of feedback loop is homeostasis? What does it mean? What do you want to stay within?

• Negative feedback loop

• When it goes up or down, signals shut down to not go too high or too low o Trying to stay within the normal range (above and below the set point)

What are the steps in homeostasis?

1. Something happens to change normal state (stimulus)

2. Sensory system (sensor) is activated

3. Response system (effector) is activated

4. Response is sent to adapt to the irregular state

5. Normal state returns

What are the four key points of homeostasis?

1. Sensor: constant monitoring

2. Integrating Centre: to coordinate

3. Response System: to change

4. Most systems operate in a negative feedback manner

What are the major nervous and endocrine regulatory systems?

• Skin

• Cardiovascular

• Renal

• Digestive

• Respiratory

• Musculo-skeletal

What are the regulated factors that the major systems use?

• Water

• Electrolytes / pH

• Nitrogenous compounds

• Oxygen

• Carbon dioxide

• Temperature

• Toxicants

Which system is homeostasis mainly maintained by?

- The endocrine system

What are some diseases / illnesses (endocrine disorders)?

• Diabetes mellitus

• Thyroid disorders

• Endocrine ovarian disorders

What is the difference between hyperfunction, hypofunction, and resistance in relation to hormones?

• Hyperfunction: too much hormone / activity

• Hypofunction: too little hormone / function

• Resistance: hormone amount okay, but cells are not responding properly, so too little effect

Which gland is responsible for making mediators / hormones and then releasing them into the bloodstream via the blood to influence a target cell?

- Endocrine glands

What were the steps in discovering insulin (the "chemical") was a hormone? (Classic Minkowski Experiment)

• Removed pancreas of a dog

• Dog developed symptoms of diabetes (elevated blood glucose)

• Implanted pieces of pancreas under the skin to prevent the symptoms

• Hormone was produced again

How did Banting and Best discover insulin?

- They injected it into the pancreas, and it showed preventative manners toward diabetes

Which type of cells produce insulin? Where is insulin produced? What does insulin promote?

• Produced by beta cells

• The beta cells are from the pancreas

• It promotes the absorption of glucose from blood to skeletal muscle and fat tissue

What does the inactive / resting form of insulin look like? What about the active form?

• Inactive: hexamer, with a zinc ion and histidine residues

• Active: it is a monomer (a molecule that can be bonded to other identical molecules to form a polymer)

What are the four most common hormones?

• Proteins and Polypeptides (<100 AA)

• Steroids (cholesterol derivatives)

• Amines (catecholamines)

• Amines (thyroid)

What three levels of effect do hormones have? How do they differ in regard to getting from secretory cells to target cells?

• Autocrine: occurs on the target cell

• Paracrine: acts on nearby target cells

• Endocrine: have to go through the bloodstream to get to the target cell

What do hormones bind to in target cells?

- Receptors (which are specific for certain hormones)

True or false: non-specific binding cannot occur because there is very high specificity for particular hormones?

- False. Yes, there is specificity, but hormone "overspill" can occur, leading to non-specific binding

Why is it important to have a continuous turn-over of the receptor-hormone complex?

• So that receptors can be recycled and re-signalled

• It is essential for any signalling system

Where are most transmembrane receptors (for most hormones) found?

- In the plasma membrane of target cells

Where are receptors for steroid and thyroid hormones found?

- Inside the target cells
o Thyroid \= in nucleus
o Steroid \= in cytoplasm

For transmembrane receptors, what does the hormone bind to? What does this activate?

• Binds to the extracellular domain of the receptor

• Activates one or more cytoplasmic signalling pathways within the cell

What can the cytoplasmic signalling pathways lead to?

• Phosphorylation and enzyme activation

• DNA / mRNA / protein pathway response

• Local effects in target cells

What are the five stages in the Adenylate Cyclase Pathway (outside the cell)?

1. Hormone and receptor protein dissociate G-proteins

2. Adenylate cyclase subunit activates through the binding of a G-protein

3. Production of cAMP + PPi is catalyzed from ATP

4. cAMP removes the regulatory subunit from the inactive protein kinase, binding itself to the regulatory subunit instead

5. The active form of protein kinase activates or inactivated other molecules for a hormonal response (like the phosphorylation of proteins)

Which receptors bind to epinephrine through the adenylate cyclase pathway? What does it result in?

• Beta-adrenergic receptors

• Results in activation (activate adenylate cyclase)

What are the six stages in the Phospholipase C-Ca2+ Pathway (outside the cell)?

1. Hormone and receptor protein dissociate G-proteins

2. Phospholipase subunit activates through the binding of a G-protein

3. Breakdown of membrane phospholipid into IP3 (inositol triphosphate)

4. IP3 binds to the endoplasmic reticulum

5. Stored Ca2+ is released into the cytoplasm

6. Ca2+ activated other molecules for a hormonal response

Which receptors bind to epinephrine through the Phospholipase C-Ca2+ pathway? What does it result in?

• Alpha-adrenergic receptors

• Results in activation (activate phospholipase C)

What are the steps in steroid hormone receptor binding (within the cell)?

1. Steroid hormone enters target cell bound to a lipophilic plasma carrier protein

2. Steroid hormone binds cell cytoplasm receptor

3. It translocates to nucleus and binds to DNA (acting as a transcription factor)

4. It stimulates gene transcription

5. Protein synthesis occurs and there is protein product

6. Steroid hormone is produced for a response in the target cell

What are the steps in thyroid hormone receptor binding (within the cell)?

1. Thyroxine (T4) dissociates from its carrier and passes through plasma membrane of target cell

2. T4 is converted to triiodothyronine (T3) in the cytoplasm

3. T3 uses binding proteins to enter the nucleus

4. Hormone receptor complex binds to the DNA

5. Synthesis of mRNA occurs

6. Newly formed mRNA codes for protein synthesis

7. Thyroid hormone is produced for a response in the target cell

What is the main route from the hypothalamus to the tissue response?

1. Hypothalamus

2. Through blood vessel to anterior pituitary cells

3. Through main circulation to target tissue a. Peripheral endocrine gland to main circulation to tissue response b. Non-endocrine tissue straight to tissue response

What is the pituitary protected by?

- Bone

What connects the hypothalamus to the pituitary?

- Infundibulum (stalk)

What are the two parts to the pituitary? What are they?

• Anterior pituitary: endocrine gland

• Posterior pituitary: extension of neural tissue

Where is Anti-diuretic (ADH) and oxytocin produced?

- In the hypothalamus

Where is Anti-diuretic (ADH) and oxytocin released?

- In the posterior pituitary gland

What are the seven (two inhibitory, five releasing) hypothalamic hormones?

• Dopamine / PIH (prolactin inhibitory hormone)

• PRH (prolactin releasing hormone)

• TRH (thyrotropin releasing hormone)

• CRH (corticotropin releasing hormone)

• GHIH / somatostatin (growth hormone inhibitory hormone)

• GHRH (growth hormone releasing hormone)

• GnRH (gonadotropin releasing hormone)

What are the five (with one being split into two) anterior pituitary hormones?

• Prolactin hormone

• TSH (thyroid stimulating hormone)

• ACTH (adrenocorticotropic hormone)

• GH (growth hormone)

• Gonadotropins o FSH (follicle-stimulating hormone) o LH (luteinizing hormone)

What are the three main pars in the pituitary gland (not anterior / posterior)?

• Pars Tuberalis

• Pars intermedia (skin colouring, other things)

• Pars Distalis

True or false: pituitary glands differ in structure look for different animals?

- True

What is CRH? Where is it located?

• Corticotropin releasing hormone

• Brain / hypothalamus

What is ACTH? Where is it located?

• Adrenocorticotropic hormone

• Anterior pituitary

What is cortisol?

• A glucocorticoid

• A chronic stress hormone

• The endocrine target

What is the main pathway from corticotropin releasing hormone to the tissues?

1. Hypothalamus a. CRH (corticotropin releasing hormone)

2. Anterior pituitary a. ACTH (adrenocorticotropic hormone / corticotropin)

3. Adrenal Cortex a. Cortisol (steroid hormones) (can go back to anterior pituitary or impact other tissues)

4. Many tissues

What are the steps in the central stimulatory control of the CRH (in the hypothalamic paraventricular nucleus)?

• Stimulation starts in the brain (noradrenergic)

• Stimulates pre-proCRH gene and protein expression of 196AA

• It is processed to CRH which is 41AA

• It stimulates the pulsatile release of CRH

What are the inhibitory influences of the CRH synthesis and release in the hypothalamus?

- Physiological levels of cortisol
o Can inhibit the release of CRH (and possibly inhibit the pre-proCRH gene expression)

Where is CRH produced? What is it produced by?

• Within the parvocellular nucleus of the hypothalamus

• Produced by parvocellular neuroendocrine cells

Where is CRH released from? Where is it released to?

• Released at the median eminence (base of the brain) from their neurosecretory nerve terminals

• Released into blood vessels in the hypothalamo-pituitary portal system

Where do the blood vessels carry the CRH peptides to?

- The anterior lobe of the pituitary

What is stimulated at the anterior lobe of the pituitary from CRH peptides? What do they secrete?

• Corticotropes

• Secretes adrenocorticotropic hormone (ACTH)

What is the ACTH? What does it do?

• Adrenocorticotropic hormone

• It regulates adrenal cortex function

What are convertases? What do different convertases give rise to?

• They are enzymes that cleave POMC (proopiomelanocorticotropin)

• Different convertases give rise to different products

What are the two tissues of the adrenal gland? Do they merge during development?

• Adrenal cortex (outer side)

• Adrenal medulla (inner side)

• The two embryological distinct tissues merge during development

What are the functions of the adrenal cortex?

- Steroid factory

Which types of steroids are produced / secreted from the adrenal cortex? Are they controlled by ACTH?

• Glucocorticoids - yes controlled by ACTH o Ex. cortisol

• Mineralocorticoids - no, controlled by renin-angiotensin system, not ACTH o Ex. aldosterone

• Sex steroids - yes controlled by ACTH o Ex. testosterone

What is the importance of the adrenal medulla?

• It secretes catecholamines

• It is like the modified sympathetic ganglia

What catecholamine does the adrenal medulla secrete?

- Epinephrine

What are the different zones of the adrenal cortex?

• Zona glomerulosa

• Zona fasciculata

• Zona reticularis

What is the pathway of the zona fasciculata from cholesterol to cortisol?

1. Cholesterol

2. Pregnenolone

3. 17 OH-Pregnenolone

4. 17 OH-Progesterone

5. 11-Deoxycortisol

6. Cortisol

What glucocorticoid is dominant in humans?

- Cortisol

What glucocorticoid is dominant in rodents?

- Corticosterone

What is the pathway from cholesterol to corticosterone?

1. Cholesterol

2. Pregnenolone

3. Progesterone

4. Deoxycorticosterone

5. Corticosterone

Why is cortisol, an adrenal glucocorticoid, essential for life?

- Helps maintain homeostais
o Protects against hypoglycemia (low blood sugar) by promoting gluconeogenesis (increasing blood sugar)
o Plays a role in immune system, bone, and muscle
o Glucocorticoids are used as agents to regulate inflammatory response (to drive down high levels)

Why are high cortisol levels bad?

• Causes breakdown of skeletal muscles

• Suppresses immune system

• It is catabolic on bone

• Affects brain function negatively (mood, memory, learning)

What syndrome can high levels of corticosteroids in the blood cause? What are the two levels of this syndrome? What differentiates the two levels?

• Cushing's syndrome (primary) - results in excess cortisol, ACTH, or CRH levels

• Cushing's disease (secondary) - results in tumor in pituitary gland, large amount of ACTH, causing adrenals to make too much cortisol

• To distinguish: higher ACTH = diseased form

What are the symptoms of Cushing's syndrome?

• Changes in carbs and protein metabolism

• Hyperglycemia

• Hypertension

• Muscular weakness

• Puffy appearance

• CNS disorders (depression, decreased learning, memory, etc.)

How can you treat Cushing's syndrome?

• Surgery to remove pituitary or adrenal gland

• Medical management of signs and symptoms (ex. insulin for diabetes)

What can happen if Cushing's syndrome escalates?

- The disease worsens, overall help can deteriorate
High blood pressure that can lead to strokes or MI

What is the cause of hypocortisolism (Addison's disease)?

- When there is adrenal insufficiency, cortisol levels become too low

What are the causes of Addison's disease?

• Genetics

• Autoimmune destruction of adrenal cortex

• Acquired (developed) o Ex. high steroid doses

What type of rhythm does the adrenal cortisol secretion follow?

- A circadian rhythm

When during the day is the lowest level of cortisol? When is the highest?

• Lowest: sleeping

• Highest: when you first wake up

What causes insomnia?

- High cortisol levels around sleep time

What affects does pituitary pars intermedia dysfunction (PPID) have in horses?

- Abnormal cell growth (hyperplasia and hypertrophy) of the pars intermedia of the pituitary gland

What does hyperplasia and hypertrophy of the pituitary gland lead to for the adrenal glands, immune system, and blood glucose?

• High secretion of cortisol by adrenal glands

• High blood glucose and suppression of the immune system

What are commons signs of PPID?

• Abnormal hair growth

• Muscle atrophy

• Excessive sweating

• Fat pads on neck, tail, head, and around the eyes

• Pot-bellied appearance

What is the treatment for PPID?

• Drug (pergolide)

• Exercise / diet

What is the route down the thyroid axis from the hypothalamus?

1. TRH (thyrotropin releasing hormone)

2. TSH (thyroid stimulating hormone)

3. Thyroid gland a. Thyroid hormone

4. Many tissues

Where is the thyroid located?

• Just below the larynx (voice box)

• On either side of the trachea

How many lobes does the thyroid have?

- 2

What are the lobes of the thyroid connected by?

- The isthmus

True or false: the thyroid is the smallest purely endocrine gland (20-25 grams)?

- False. It is the largest purely endocrine gland

What do the follicles in the thyroid axis take up from the blood?

- Iodide (I-)

Where does TPO help attach iodide to a tyrosine residue in thyroglobulin? Hint: starts with a "C"

- In the colloid

What is thyroglobulin made up by? What amino acid side chain is found on its long peptide chain? Where is it found?

• Follicle cells

• Tyrosine side chains

• Found in colloid

How is iodide (I-) brought from the blood into the follicular cells (what type of transporter)?

- A sodium-iodide transporter

How is iodide (I-) brought from the follicular cells into the colloid (what is the transporter called)? Hint: starts with a "P"

- Pendrin

What converts iodide into iodine before adding it to thyroglobulin?

- TPO (Thyroid peroxidase)

In what two ways can iodine attach to thyroglobulin via the tyrosine rings?

• MIT / Monoiodotyrosine (1 iodine on a tyrosine ring)

• DIT / Diiodotyrosine (2 iodine on a tyrosine ring)

What do enzymes in the colloid modify the structures of MIT and DIT into?

• T3 (triiodothyronine)

• T4 (tetraiodothyronine)

What are the five main steps of the production of a thyroid hormone?

1. Start as iodide (I-) in the plasma

2. Convert to iodine in the colloid with the help of TPO (thyroid peroxidase)

3. Attach to tyrosine amino acids within the thyroglobulin molecule (to make MIT or DIT)

4. Bind MIT to DIT or DIT to DIT to make T3 and T4 (which are bound to thyroglobulin

5. Endocytosis out of the membrane when stimulated by the anterior pituitary thyroid secretion hormone

What is the carrier protein that \>99% of thyroid hormones in blood circulation use for transportation? (Hint: TBG is the short form)

- Thyroxin-binding globulin

True or false: Only bound fractions of thyroid hormones are biologically active

- False. Only free fractions are (so it has to lose the carrier protein to produce effects in target cells)

What type of secretion is TRH: pulsed or constant?

- Pulsed secretion (not constant)

What happens to our thyroid hormone production when we age?

- It is often impaired with age (higher levels when we are younger)

Does stress and cold increase TRH levels?

- Yes

During the circadian rhythm of the thyroid hormones in humans, when is secretion the highest?

- Between 10am - 2pm

Why is secretion of the thyroid hormone highest between 10am - 2pm?

- Because thyroid hormones elevate our basal metabolic rate (BMR)

What is basal metabolic rate?

- The resting rate of calorie expenditure by the body

True or False: circadian rhythm of thyroid hormones secretion is highest during the day for mice/rodents?

- False. It is at night instead