ANBI Module 1

Endocrinology

the study of the endocrine glands and their secretions

Endon + krinein =

within + to secrete

Endocrine glands

ductless glands that secrete hormones into the blood

Classical endocrine secreting glands

• Thyroid

• pituitary

Clinical endocrinology

Ethiology and treatment of human endocrine diseases

comparative endocrinology

• Learn more about the functions of hormones

  • How animals adapt to dissimilar enviros

Behavioral endocrinology

how hormones regulate behaviour

Endocrine toxicology

• endocrine disrupting chemicals and impact on humans and animal health

Hormone classical definition

• A substance secreted by specialized cells and released into a vascular system (bloodstream) or tissue fluid causing a response in target cells elsewhere in the body

• Response is mediated by receptors specific to hormone in target tissues

Issues with the hormone definition

• not always produced by glands

• not unihormonal

• multiple production sites

• transport not only thru blood

Major functions of hormones

• growth and dev

• homeostasis

• metabolism

• behavioral regulation

• immune function

Why do we have endocrine system

• multicellular forms need a way to coordinate and comm

• chemical signalling

• compliments nervous system

3 components of endo system

1. Gland/cell (secrete hormones)

2. Hormone (chemical products, released upon stimulation)

3. Target organ (express hormone specific receptors, biological response)

Exocrine glands

release secretions via a duct into an epithelial surface

Epithelial cells

• skin cells but not necessarily on outside

  • GI tract, resp tract

Endocrine glands

• ductless and release substances directly into blood/lymph

• water sol (exocytosis)

• lipid sol (diffusion)

Hormone classification based on

• type of signaling

• chemical structure

• solubility

solubility of hormones

• water vs fat sol (type of receptor)

• blood is mostly water

  • water sol receptors on outside of cells bc cant go thru lipid membrane

Endocrine signaling

hormones enter bloodstream/lymph and bind to hormone receptors in target cells of DISTANT organs

Endocrine signaling ex.

Beta cells in islets of Langerhans in pancreas produce and release insulin into blood where it travels to many tissues including liver signaling it to store glucose in form of glycogen

Paracrine signaling

hormones bind to cells near the cell that released them (same organ/tissue), often degrade quickly or taken up regularly (interstitial space)

Autocrine signalling

hormone produced biological effect on same cell that it has released it

Autocrine signaling ex

• lining of mammalian endometrium responds to oxytocin to cause production of prostaglandins (cause contractions)

• tumor cells (estrogen in breast cancer cells)

• growth hormone in pituitary cells

Intracrine signaling

• when hormone is synthesized and acts intracellularly

  • DOES NOT leave cell

Intracrine ex

• Precursor sex steroid hormones are synthesized and then are converted by enzymes to active androgens/estrogens which bind to receptors within the same cell

• Vit D (calcitriol) converted to its active form within target cells and acts intracellularly

Neuroendocrine

chemical is produced by neuron or nervous tissue and is released into bloodstream to act on another cell type

Neuroendocrine ex

• Adrenalin, dopamine, oxytocin

Hormones vs neurotransmitters

• endocrine cells vs neurons

• vesicles, diffusion vs action potential, vesicles

• variable distance vs short

• slow speeds vs fast

• depends on receptor vs specific to post synaptic neuron

Peptide and protein hormones

• proteins are more complex

• common hormone type

• made of chain aa

• preprohormones → prohormones → active hormones

• stored in secretory vesicles and released by exocytosis

• water sol

• act quickly, short half life

hormone processing

• uses enzymes on aa hormone

  • until end product, are inactive

Preprohormone

large, inactive precursor

Prohormone

smaller, inactive (proteolytic, post translational mod)

Peptide/protein hormones

bind surface membrane receptors, cellular response thru signal transduction system

peptide/protein hormone processing and release steps

1. mRNA on ribosome binds aa into peptide chain called preprohormone, chain directed into ER lumen by signal sequence of aa

2. Enzymes in ER chop off signal sequence creating inactive prohormone

3. Prohormone passes from ER thru golgi

4. Prohormone passed from Er through golgi

5. Vesicles contain enzymes and prohormone bud off golgi, chop again into active peptides

6. Vesicles release contents by exocytosis into extracellular space

7. Hormone moves into circulation for transport

Processing of insulin

1. Preprohormone of insulin translated in ER and peptidase cleaves the signal peptide

2. Folding of prohormone and formation of disulfide bonds, C -peptide plays essential role in orenting 2 chains of insulin during step

3. Prohormone secreted into golgi

4. Packaged into secretory vesicles

5. Prohormone convertases create separate and distinct insulin and c peptide molecules

6. Insulin and c peptide remain in secretory vesicles of B-cell until release

   • Blood glucose stimulates insulin release

Where is insulin produced and what cells make it

pancreas and langerhan cells

Insulin is an example of

regulated secretion

c-peptide

• is released w insulin and goes into blood

  • important in metabolism and used as measurement guide for blood insulin and glucose to diagnose diabetes

Peptide/protein hormone secretion

can be regulated or constitutive

Regulated secretion

hormone waits until signaled to release (insulin, growth hormone)

Constitutive secretion

hormone is always being secreted (ex. euthropretin RBC production in kidneys)

aa derivatives (amine hormones)

• Derived from aa, normally tyrosine but also tryptophan (precursor to serotonin and melatonin) and glutamic acid (converted to histamine)

• Sig smaller

ex of amine hormones

Norepinephrine and epinephrine, dopamine, thyroid hormones (metabolism regulators) and melatonin (circadian rhythms)

catcholamines

need vesicles for exocytosis - hydrophillic (water loving)

Thyroid hormones

lypophillic (fat loving), like steroid hormones

steroid hormones

• Cholesterol derived

  • Lipophilic and easily crosses membranes

  • Not translated from DNA - use cholesterol available in cells

  • Fat

  • Lipophilic and can cross cell membrane

  • Blood is aq so need carrier proteins in blood to move

  • Act on receptors inside cells

• Bind carrier proteins in blood

  • Longer half life

• Cytoplasmic or nuclear receptors

  • Genomic effect to activate or repress genes for protein synthesis

  • Slower acting process

• But can also bind to cell membrane receptors

  • Nongenomic responses

Ex of steroid hormones

• Glucorticoids

• Mineralocoricoids

• Androgens

• Estrogens

• Progestrogens

Cholesterol importance

• parent compound for all steroid hormones

• cascading effect depends on converting enzymes

cortisol chronic stress hormone is in

mammals

corticosterone is in

verts other than mammals

Eicosanoids

• Modified 20 C fatty acids w complete/partial C ring and 2 long C tails

• All derived from arachidonic acid (part of phospholipid bilayer of membrane)

  • Lipophilic

• important in many physiological processes

Prostoglandins

• constriction and dilation of smooth muscle cells

  • asthma and anaphylaxis

Leukotrienes

• inflammation compounds immunity

NSAIDS and COX2 inhibitors

• drugs to prevent making of prostaglandins and leukotrienes to block enzymes, preventing inflammation

Eiocasinoid hormone ex

• Prostoglandins

• Leokotrines

• NSAIDs and COX2 inhibitors

• rapid acting and paracrine

Arachidonic acid cascade

• Phospholipase A2 catalyzes the hydrolysis of a bond In membrane phospholipids

• Rxn released arachinonic acid and free fatty acid

• AA precursor to eicosanoids including prostoglandins and leukotrienes

• Rapidly inactivated by being metabolized -> typically active for only a few seconds

Estrous cycle

• Estrogen (steroid) goes up right before LH (release of egg - developing in follicle of ovary) tertiary follicle

• Progesterone (steroid) goes up from corpus luteum (shell from which egg ovulated from) mid cycle also prevents another ovulation

  • Thickening of uterine lining, in prep for potential embryo dev

  • Fert may or may not happen

• Prostaglandin released from endometrium cells to cause corpus luteum to degrade and tell repro tract no pregnancy

• Includes

  • Ovary + egg

  • Smooth muscle cells of uterine lining that secretes hormones

hormone structure importance

1. Transport and solubility - structure (polar vs nonpolar) dictates whether it travels freely in blood or requires carrier

2. Stability and duration - structural features influence degradation rate and half life, affecting how long the hormone lasts

3. Cell entry and signalling - hydrophobic hormones can cross membranes easily, while hydrophilic hormones need receptors on cell surface

4. Receptor binding and function - shape chemical groups determine receptor specificity, which drives physiological effects

5. Evolutionary insights - conserved structural motifs across species reveal evolutionary relationships and functional importance

physiologic effects of hormones depend largely on

their conc in blood/extracellular fluid

disease arises when hormone conc are

to low or to high

Male and female reference ranges are diff bc

• they have other hormones circulating and they interact diff in the body

conc of hormone as seen by target cells determined by

1. Rate of production

2. Rate of delivery

3. Rate of degradation and elimination

elimination or hormones

• kidneys → urine

• liver → fecal excursion thru GI tract

hormone lifecycle

• Endocrine cell -> hormone (pink sphere) -> released into circulation (blood)

  • -> bind to binding protein in blood (lipophilic hormones, steroid, thyroid)

  •  -> liver and excreted via GI tract, liver can change hormone to do something else (shape) act on target cell to fit receptor

  • -> maybe not changed/metabolized and go directly to target cell

  • -> kidney and excursion by urine

  • -> feedback regulation (specific control) alter cell that made it to turn on more synthesis or turn down

rate of production/secretion

• pos and neg feedback circuits

stimulation of hormonal production

1. humoral

2. neural

3. hormonal

Humoral stimulus

• hormone release caused by altered levels of certain critical ions or nutrients

• not an endocrine signal but something in blood tells endocrine cells to make hormones (glucose and Ca2+)

neural stimulus

• hormone release caused by neural input

• nervous system/cell send messaged to endocrine cell to produce hormone (acetylcholine is NT, released at end of nerve that inervate adrenal gland to make hormone fight or flight)

Hormonal stimulus

• hormone release caused by another hormone

  • Thyroid stimulating hormone (TSH) - thyroid gland

  • ACTH

    • Testosterone - stimulated by LH

JUST KNOW THIS

Feedback regulation

allows the body to correct any type of hormone release after a stimulus

Negative feedback regulation steps from homeostasis

1. Imbalance of endocrine gland or tissue hormone level

2. Hormone release

3. Correction

4. Negative feedback

Glucocorticoid negative feedback ex

• gluco low conc of stress hormone detected by hypothal via sensors in blood vessels

• hormone release of CRH and ACTH cascade triggers adrenal gland to release more gluco into blood

• conc of gluco in blood increases to normal and hypothal senses normal conc and stops CRH

Negative feedback …

shuts off and happens most of the time

Positive feedback

• further stimulation of the hormone which was the og source of the signal

positive feedback vs stimulation

• positive feedback reinforces that hormone release

• stimulation is the original stimulus that triggered the hormone release

Positive feedback estrous/menstral cycle ex

• Follicular phase- hypothal releases GnRH to anterior pituitary, release of FSH, LH to ovary, estradiol neg feedback to pituitary

• Midcycle same thing except estradiol is pos feedback to pituitary

• Luteal phase - same except neg feedback of progesterone to pituitary

Positive feedback in estrous cycle leads up to

• ovulation

  • estradiol stimulates more FSH and LH production so eggs grow

albumin and transthyretin

• bind small ligands, gen transport mol

  • moves basically everything in body

Delivery

• higher blood flow → delivers more hormones than low blood flow

• circulate free or bound to large protein

specific transport proteins

1. Corticosteroid binding globulin (CBG)

2. Thyroxine binding globulin (TBG)

3. Sex hormone binding globulin (SHBG)

Plasma proteins

control lipid sol hormones to get thru capillaries and be delivered to tissues

Why do males and females have diff drug dosages

• diff amounts of binding proteins in bodies

• drug delivers needs binding proteins, hormone delivery will be diff

Which hormones sol can travel freely but cant enter cells without receptors

hydrophilic

free hormones is the _____ form and can

bioactive form, leave blood into target tissues and is free to bind receptors

% of free proteins is

2

when free hormones go into tissues what happens

bounded hormones are released to balance the conc and stimulate tissues to make more hormones

hormones change from what sol when metabolized and excreted from body

lipophilic → hydrophilic

How are hormones degraded

• Some are metabolized by their target cells

• Some metabolized by enzymes in circulation

• Many metabolized by enzymes in liver and kidneys

• Most excreted via kidneys (some via liver -> bile)

half life

time during which the conc of hormone decreases to 50% initial volume

half lives of amines vs thyroid vs polypeptide/protein vs steroid

• amines - very short min

• Thyroid - long days

• Pp and proteins short - min

• Steroids - medium min to hours

Metabolic clearance rate

removal of hormones from circulation, the volume of plasma cleared of the hormone per unit time

Short half life =

leaves quick, high MCR

long half life =

leaves slow, low MCR

Thyroid has a ____ protein binding, _____ half life and _____ MCR

high, long, low

Steroids have a _____ protein binding, _____ half life and _____ MCR

low, short, high

Metabolic degradation is mainly in the ____ thru enzymatic processes

liver

Liver metabolic degradation processes

• Phase I - breakdown (oxidation, reduction)

• Phase II - adding something (methylation, sulfuration)

Excretion of hormones thru

bile or urine

hormone breakdown not excreted

target cell may internalize hormone and degrade it and use for other processes