Physiology (Endocrine) Flashcards
Pre Hormones vs. Hormones
Pre-hormones - not water soluble = need a carrier protein
Hormones = free hormone that is active ad availible for target tissue
Release of the carrier protein = based on equilibrium between the pre-hormone and hormone
Endocrine
Secretions that stay in the body (secreted into the blood)
- Endocirnology = Study of signlaing (Signal goes to blood –> goes to target tissue -> signal causes effect)
- Endocrine = humeral
Function - Endocrine glands use hormones to regulate bodily function
Exocrine
Secretions go outside the body or to lumen (Ex. sweat going t sweat galnds or bile or pancreatic enzymes)
Basic science/Clincal of Endocrine
Endocrinology is clinically and basic science orientated
Basic science of endocriniology (overall)
Includes principals of homrone synthesis + secretiono/action + feedback regulation/homeostais + receptor binding/intracellular signaling –> ALL fundemental concpets that are critical to the fundation to understadning many specialties and scinetific disaplines
Clincal of Endocrinology
Clincal endocrinology = specialty of internal medicine concerned with dieases that affect the “classical” endocerine organs
- Also looks at hormone regulation and feedback
Can also encompess obesity + osteopereosis + lipid disorders + hypertension
- Can include bone dieases + lipid disorders
Can overlap with other speciaties (ex. Oestoperosis and rickets = Endocronology + renal OR can iber lap with gynology/urogology (reproductive endocrinology)
Classical endocrine organs
- Thyroid
- Parathyroid
- Pituitary
- Adrenals
- Pancreatic islets
- Gonas (overy and testes)
Endocrinology Basic Science
Basic science of endocronology begins with the study of hormones and their actions on organ tissues
Looks at:
1. Receptors + intracelular signlaing + trasncriptional regulation
2. Intracellular communication within tissues and between organs
Discovery of new hormones and emergnce of diseases means the feild is always evoloving
- Example - Leptin is new
- Example 2 - Finding new actions of hormones
Endocrone vs. nervous system
BOTH - major communication systems in body
Endocrone - Release of homrone to the blood
- Affects distant tissue + indirect affect (lack direct contact)
- Secretion of hormones that go through the blood is more gradual
- Can have a sort effect (rapid acting with rapid effect) or long effect
Nerve
- Loclized effect +
- Direct communication between nuerons and each other or neurons and target tissue by innervation
- Fast - because electrical signals
Hormone
Chemical signal secreted into the blood stream to act on distant tissues to regulate somthing in the target cell
Types of hormones
- Act on nuclear receptors
- Act on surface receptors
Different based on where action occurs in cells
Nucelar receptor hormones
Nuclear = class of classical receptors
Includes:
1. Thyroid hormone (derived from tyrosine)
2. Steroid hormone (derived from choletral)
- With intact steroid nuceus (Ex. Gonadal ad Adrenal steroids)
- With borken steroid nucleus (Vitamen D)
BOTH = cross the lipid barrier –> bind to intracellular recepter
Surface Receotor horomone
Includes:
1. Polypetides
- Some are small (Ex. TRH is 3 Amino Acids)
- Some are big (Ex. GH is 200 AA)
- Some are Glycosytlated (Ex. TSH + FSH + LH + hCG)
2. Monoamines and derivatives (Ex. Seratonin + dopamine + norepinephrine + epinerphines)
3. Prstogalndins
ALL - bind to the outside of cell (don’t pass the lipid membrane) ; all require signal transduction via second messengers intracelularly
Nucelar receptor hormone structures
Thyroid homrone - derived from Amino Acid
Steroid Homrone - derived from chlestral (have cholestral backbone + have substituents)
- Substituetnts define how it binds to intraceular recptor –> bind vcausing confirmational change –> causes effect
Nuclear receptor superfamily
- Sterroid homrone receptors (includes sex hormones)
- Heterodimeric recpetors - bind in heterodimer with another heterodimer receptor
- Orphan Receptors - don’ have known obvious ligand
IMAGE - has list of all of them
Homrones that act on the cell surface
Left side - peptide hormoe
Right - shows epinephrine + norepinephrine (Amine derived)
Mechanism of hormone (Nucelar receptors)
Have residue within cells
Receptors = bind with ligand to nucleas –> regulate trasncripton through hormone activation –> end have phenotypic change (hormone effect)
IMAGE - shows process
Mehcnaism of cell surface recptors
Growth factor receptor = reacts with tyrosine kinase
Signal using signla trasnduction mediater
Hormone = ligand for rceptor –> binds –> acts on target tissue that has the cell surface receptor
Types of cell surface receptors
Example:
1. Growth factor receptor
2. GPCR - svene mebrane spaning domain receptor (Ex. NE, TRH, LH)
Where do hormoes act
Can divide classical hormones based on distance:
1. Endocrine
2. Paracrine
3. Autocrine
Endocrine hormines (in terms of diatnce)
The hormone is secreted into the blood and transported to anotheer site (target) where it exerts function (stimulatory or inhibitory)
Classical hormones = often affect distant organs
Paracrine
The hormone acts locally on nearby cells
- Not traveling far in the blood
Example - sex steroids in the overy
Autocrine
The hormone acts locally on the cell that has produced it
Example - Insulin
- Pancreatic islets = have endocrine subtype (autocrine) – signal to each other in a autocrine/oaracine fasion (not going into blood stream)
Where do hormones come from
Overall - there are sevral endocrine glands
- Have secretion of hormone from glands that make specific hormones
Glands are:
1. Ductless (as oppose to exocrine which have ducts to get things to the GI tract)
2. Highly vasculrized
- Example - pancreatic islets see 20% of the blood volume at any gven point
- Needed to the hromones can ho into the blood and signla to the rest of the body
There are 6 clasical endocrine glands - descrete organs with hormone secreaton as their primary function
- Also have many “non-clasical” endocrine organs that have other primary functions
Hormone secreation
- Basal Secretion - always being secreted at low levels
- Stimulated secretion (tonic) - stimulated by different things to secrete hormone
Secrete hormon from pool of prescuror hrmone into the blood
- Secretion can be tonic or basal
Example - Insuline secretion is basal and glucose stimulated
Stimulated secretion
Have a chemical sensor that increases or decreases secretion
- BUT not electrical = not like nerves
Pulses of hormone secretion
Pulses may have different periodicity - Flucuation of homrone in the blood can be stocahctic (random) OR can be periodic
Example:
1. Circa-horal - every hour
2. Cia-dian - Every day (Ex. Ciacadian rhythm - Corisol + testostrone)
3. Ci-Trintan - Every month (Ex. menstral cycle)
Free Hormones
Active fraction of hormones for celular action and feed back
- Often Amine and Polypeptide hormones because they are water soluble (have a shorter hald life) (EXPPTION is insuline like growth factos bound to IGFBP)
In the lab you should measure free hormone but that is not always possible
- If you measure total hrmone and there is a carrier protein abnormality the total hormone may not refect the free hormone
Inactive hormones
Fraction of hormones that are biund to carrier protein largest fraction of hormone)
- Hormones that are protein bound are cleared more slol from circulation by the liver and kindeys (have a longer half life) (ex. thyroid + steroid)
Bound and free fractions of hormone are in equilibrium
Circulation of steroid and thyroid hormones
Steroid and thyroid homrones = circulate bound to carrier proteins because they are not water soluble
Example -
1. Thyroglobulin bins to T3 and T4
2. SHBG bines to testostrine and E2
3. CBG for cortisol
4. Non-specific Albumin and pre-albumin
EXCEPTION - mineracortoid steroids don’t have a carrier (Ex. aldostrone)
Homrone action
Hormone ats as ligand on hormone receptor
- Only a small fraction of circulating hromone is taken up by the target tissue
- Bulk of clearance is dne by the liver and kidneys
- Have many kinds of enzymatic reactons (Ex. Hydolysis + Oxidation + Hydroxylation) –> allows hormones to be cleated by the liver?
- Smal fraction is extreted intact in urine or feces
Have:
1. Agonist
2 Partial Agonist
3. Antagonist
***Can be based on binding seperatley
Hormone regulation
Most hormones have another hormone that regulates their secretion
- Interaction between hormones = Feedback
- Most organs secrete hormones AND wil scerete asecond ormoen or a byproduct that will regulate the first hormone
Two types:
1. Stimulatpry (Trophic) - Hormones that stimulates the secreation of another hormone
2. Inhibitory - Hormone tha inhibits the secretin of another hormone
Negative feedback
A trophic hormone inducdes the secretaion of a second hormone which in turn inhibits the secretionn of that FIRST hormone
- Taregt releases a hromone that tells intital cell to stop making the hormone
- Increase in Homrone A leads to increase in Hormone B which inhibits production
More common
Positive Feedback
Amplifies abundent signals
Target cell makes substance to tell the initial cell to make more hormone
- Increase in hormone further increases producton loop
Can lead to runaway affect
Overvoew of the 6 Classicla Endocrine organs
Pituity - Secretion hormone that regulates other endocrine glands + tissues
Functional Charcterization of Hormones
ALL regulates by multiple hromones from diffreent places
Functional Characterization of Endocrone diseases
- Hypofunction
- Hyperfunction
- Hormone release resistce syndromes
Hypofunction
Overall - Hormone Deficeincey
Primary - the primary (or target) gland itself is defective (Ex ample - primary gland is destroyed by autoreactive lymphocytes such as in Hashimoto or Addison)
- Deficney syndome of target
- Example - thyroid not making thyroid hormone BUT signal from pititary is fine (occurs in hypothyroidism)
Secondary - The trophic hormone in the pituitary us defcetive (pituitary is not sending signal to tissue)
Tertiary - The trophic hormone in the hypothalumus is defcetive
Hyperfunction
Overall - Hormone excess (runaway product of organ)
Primary - the primar (target) gland itelf is hyperctive (Ex. Graves)
Secondary - The trophic hromone in the pititary is over produced
Latrogenic/Fictious - Administartion of synthetic hormones (causes hormone exces)
- Intentially (by a physican) - Iatrogenic
- Without Physcian knowldge - Ficticous
Hormone Reisstnce sydromes
Hormone is produced in substantial qunatities but is inactve or has reduced activity
- Not issue with hormone production but repsponse in target tissue is low
Can develope resistnce because:
1. The hormone itself is abnormal
2. The receptor for the hormone is blocked by antibodies
3. The receotor is abnormal
4. Issue downstream of receptor that blocks hormone activity
Example - Diabetes –> have the same amount of insulin hormone but it doesn’t have enough activity = don’t cause glucose uptake
(Check clide 24 because cut off at bottome)
Overview of pititary functions
Hypothlamic Hypophysiotrophic hormones
Hypothelumus regulates pititary
- Growth hormoone releaseing homrone
- Somatostatin
- Corticotropin releasing hormone
- Gonadotropin releasing hormine
- Thryotripin releasing ormone
- Prolactin Inhibiting Hormone (dopamine)
Puitary Anatomy (location)
Pituitary - Sits at the base of the brain
- Connected to the hypothalymus
- Sits behind the sinus of the nasal passage
- Highly vaculirized
- When have tumor/englargment of pituitaruy then you have space occupencey issues (have improtant things nearby that pitautray can put pressure on (Example - optic chiasm = lose vision OR pressure on vessels nearby OR have functional loss if press on cranial nerves nearby
Pituitary Antomy
Stall (infundibulum) is composed of:
1. Mediam emince of the hypotheluumus
2. Stem that arises from it
3. Pars tueralis of the anterior hypophyis
Stalk + Posterior lobe = neurona; in origin
Anterior Lobe = secretes most pituitary hormones
Overall - pituitary is very small
Pituitary Histology
Pituitary cells
Each pituitary homrine is made by each type of cell
Somatotrophes = Gorwth Secretion
Lactotrophes - PRL-secreting
Corticotrophes - ACTH-secreting
Gonadotrophs - LH-FSH secreting
Thyrotropes - TSH-secreting
Hypothalumus-Pititutary Growth Hormone
Pituitary somatatrophes scerete growth hromone –> act on the main tissue (Example - developing oranisms need linear forowth and development)
- Function is meidated by acting on liver –> get induction of GH factor 1 = has effect
GH = harder to capture on tests –> look at IGF1 levels because they are mre stable and representtative of GH axis
Giagantism
Have Excess of growth hormones before bones are fused = have linear growth
Ex. Tallest perosn = gigantism
Acromegly
Too much growth hormone as an adult = get growth of hands and feetor facial featires or internal organs
Prolactin
Polypetide hormone secreted from lactotropes
Plasma hhald life of 50 minutes
Have several circulating forms of Prolactin –> explains discerpinsies between bioassay and immunoasay
- Immunoassays do not always reflect the biologic sitiuation
Made by the pititary
Growth hormone like (don’t 100% know what it is doing)
- Most recgnized for effect on lactation but could have effect on other things (affects lactogens and islets in pancreus)
Is elevated during seizure
Function of prolactin
Main function - stimulates milk synthesis in post partum period
- Induces the final differentation of milk cells that results in casein synthesis
- ALSO has a controceptive effect by inhibiting pulsatile secretion of HnRH = have no midcyle surge = no ovulation (decreased reproduction in women when scereted)
Have excess PRL in women causes oligomenorreha/amenorrea/galactorrhea
Excessl PRL in men can cause decreased libedo + galactorrhea + erectile dysfunction
Control of Prolactin Secretion
SKIPPED SLIDDE
Thyroid Physiology
Thyroid is the largest endocrine gland
Synthesizes Thyroid homrones (T3 and T4)
Thyrod homrones = contain 60% iodine (makes them unique) - used for clincal diognosis and managment
Function of thyroid hormones:
1. Promote growth and development
2. Promote Brain development
3. Regulate energy and heat production
4. Regukate metabolism + Body Temperature + Thermogensis
5. Are regulated within tissues of the body by deiodinases
What cells have a Thyroid hromone receptor
ALL cells have a TH receptor –> Can take up T4 –> converts T4 to T3 in cells
Thyroid Anatomy
Located at the base of the neck
- Highly vacsularized
Thyroid Histology
Big filled circles –> Cells surround the follciles of the stored Thyroid Homrone
- When you mobilize TH or have a disease = see loss of the prefomred store = have no bubbles
Thyroid Hormone Synthesis
Thyroid Homrone synthesis requires:
1. Iodine
2. Storage of preformed Thyroid Hormone into colloids –> some TH will be secreyed into the blood and some some are mobilized by thryoglobulin and is released to Thyrocytes
Thyroid Feedback
Thyroid = targets the pituitaru
Thyroid Stimulating Hormone = stimulates Thyroyd homrone to increase –> Increase T3/T4 –> Homrones go to body –> have negative feedback loop in pititary to decrease TSH
- Hypothamuc factir = regulates TSH
Function of Thyroid Homormone
- Normal dveelopment + growth + nueronal differentiarion
- Metablism regulation + energy regulation
- Amphibia metamorphisis
- HR
- Body temperture
- GI system speed/function
- Muscle contraction
- Skin and bone turnover
Clincal Hypothyroidsm
Dirven by immune –> immune destoys thryoid cells = get hypothyroidsm
- Have fatigure + Weight gane + dry skin
Causes Hashimotis (most common cause of Hyothyrodism)
- Have autoimmune destruction of thrypod (seen by thrmphocyte infiltration)
- Reealse natgen –> get Autoantibodies (anti-TPO) NOT care not casual but evidnece of immune autoreactivity (measure then in clinic)
Clincal Hyperthroidsm
Overactivation of Thyroid = Graves disase
Antibody is made by autoimmune bind to and stimulate Thryoropin (TSH) receotir on the surface of thryoid folicle cels –> thyrocytes to open –> get increase in Thyroid hormone NOT regulated by piuitary
- Causes Increased metabolsim –> Get swoellen thyroid + wiht loss + Increase HR + can;t sleep
- Have no stored TH in glands on pateints with Graves
Hypothalumus-Pititaru-Adrenal Gland Axis
Hypothelymas –> sents CRH to Pititary –> Pituitary send ACTN to the Adrenal Gland –> Adrenal cland makes cortisol and androgen
Adrenal Anatomy
Location - Abive or medial to the upper poles of the kidney ; Retroperitenal
Weight - 10g
Made up of:
1. Corext (outter) - 90% of weight
2. Medula (inner) - 10% of weight
- Medula and cortex secret different hormones
Lots of blood goes to the gland
Classes of hormones released from
- Mineralic - saly/water/BP levels
- Glucocortcoid - stress response
- Androgen
Aldostrone
Main Hormone Prodcuce din teh zoma glamerulosa
A signeficant percentage (30-50%) cicuate free onces secreted
- remaining majority circulates while bound the albulin and in part to CBG –> short half life (15-20 minutes)
Aldostrone = rapidly inactivated in the liver
A small amount of free aldostrone filters in the urine and can be eaisliy quantatied
Aldostrone target and Actions
Function - maintain normal Na+ and K+
concentrations and normal extracellular fluid volume
Target - Kidneys + Colone + Salivary glands + sweat glands
Aldosterone freely crosses the plasma membrane and combines to a specific mineral corticoid receptor in the cytosol –> The steroid-receptor complex moves into the nucleus where it alters the transcription rate of several genes ( Example - affects Na/K ATPase pump gene –> Na+ is taken up into the cell and exchange for K+ or H+ –> Na+ then moves to the other pole of the cell where it is transported into the extracellular fluid, helping maintaining its normal composition and volume)
Regulation of Aldostrone
Uses the renin-angiogenstin system
Not Directly regulated by the pituitar BUT regulated by the kidndeys sense of water pressure and volume
Kidneys make renin –> Renin goes to the body –> Get increase in angiogenstin 2 in lungs –> stimulates aldostrone production in the adrenal gland
Have feedback loop of B and Na/K levels
Cortisol
Synthesized by two pathways (both use 17-alpha hydroxylation_
Main pathay - startes by converting preognenolone to 17-OH pregnenoline –> then converted to 17-OH progestrone –> 21-hydroxylase then converts 17-OH progestrone to 11-deoxycortisol
Alternative pathway - converts first pregnenolone to progesterone –> convered to 17-OH progesterone –> 21-hydroxylase then converts 17-OH progestrone to 11-deoxycortisol
Defective Cortisol production
Specifc enzymatic diferences that can cause blackages to the pathway –> get defetive cortisol synthesis
Enzymes lead to clinical aparent blocks = salt wasting of verilization in kids
Stress
Physical stress (ex. surgery + flught + hypoglycemia) AND physological stress quickly stimulates the production of CRH + ACTH and therefore cortisol (within minutes)
- Increase the pathway to increase cortisol during stress
- Helps body respond to stress
IF the stress is prolonged then the circadium rythim is abolished
Prior treatmemt with high-dose glucocortorids abolshes the stres responsle of ACTH and cortisol
Cortical metabolsim
After release from cortical cells –> majority f cortisol (90) enters the circulaion and binds to corticosteroid-binding globulin (CBG) (75% bind) BUT some will bind to albumin (15%) –> CBG bound goes to cells in the body –> binds to glucocortoird receptors –> Affects stress response
- 10% of circulating crtisol is free
- Bound hormone is inactive ; free is active
Cortical = metabolized in the liverC
Cortical + Circadium rythm
Have low levels at midnight (Cortisol (and ACTH) nadir is MN to 2am) –> increase levels in early morning (ncreases to about 7am; half of the total daily cortisol output is produced in this
period) –> decrease levels over the course of the day
- Cortisol increases in response to eating + exercise + stress
Rhythm over the course of the day is disrupted in jet lag or sift workers –> re-establishing to circadium rhthym is important for avoiding issues with cortical excess
Glucocortorid (cortisol) action
Cortisol enters into the cell and binds to a glucocorticoid receotor located in the cytosol –> Hormone reetor complex enters the nuceus –> in nuceus the complex binds to a cysteine rich reginon – chealtes zinc –> assumes a zine fincer conormation (cis action)
- Hormone - reeptor Complex can also interact with other transcription factors (Ex. Nf-Kb)
END - have change in gene expression
Target of Glucocorticoids
Overall - Have lots of action on different organs
- Cushing - Excess Cortisol
- Addison - decrease in Cortisol
- Things happen if have decrease of increase in cortisol
Addisons disease
HE SKIPED SLIDE
Hypothelymus-Pituitary-Gonadal Axis
Feedback loop from HPA axis
Hypothlymus –> signla to pituitary –> stimulates pituitary to make FSH –> Promotes target gonads to make egg or sperm + to make sex hromone in target cells
Glucose Homoestasis and Diabetes
Left image - see exersions of glucose and insulin
- Normal - Increase glucose after meal = increase nutrients = stimulates islets to increase insulin = puts glucose into target tissue
- Diabetes = can’t maintain fasting blood glucose –> have excerson of glucose that are pronounced (diabetes have higher glucose)
Right - Theoretically shows that Type 2 diabetes pateints can have higehr insulin levels than controls but still have high glucose
Type 2 Diabetes
Have increase in glucose despite increase in insulin
- Example of resistnce to hormone
Type 2 = can have higher insulin that conrtols but the glucose level is still high
- Depends on when you measure over course of disease - at the late stage = production of insuline is lower relatuve to normal production
Type 1 Diabetes
NO insulin production
Glucose sensing by Beta-cell
Glucose sensing by Beta-cells leads to physiologic Insulin Secretion
Pancreatic beta cell secrete insulin –> beta cells sense glucose level in blood that reflects nutrient state (glucose ___ in beta cell is not regulated)
- Intracellularly - glucose is phospholated = traps glucose in the cell = Increase ATP:ADP ratio as glucse increase –> keep increase phosphylation = increase ATP:ADP = get depolarization of the memebrane –> voltage gated Calcium chanel opens –> get insulin exocytosis of preformed insulin
- Nueroendocrine cell - stimulated by electrical depolorizatiionn –> release trasniitted -> insulin goes to target tossues
Shows that when you eat = glucose increases = insulin increases in blood
- Increase is deteclable within minutes
Release of insulin is 1st phase ; ALSO have linger chronic secretion driven by constutive secretion
Insulin Overall
Insulin is well studied
Pre-polypeptide that loades on self ; has intramilecular di-sulfide bonds –> Insulin pre-polypeptide is cleaved = get cypeptis –> have insulin molecule at A chain and B chain and disulfied bonds
Treating Diabetes
Glucose = stiulates a rapid insulin release
Diabetes treatment challenge - try to recopitulate insulin pjarmocologially BUT it is hard to do with one molecule
Result - they made a mocleule with long acting (bsal avtivating) and shor acting (covers meal time excersions)
Making insulin for treating Diabetes
Have long acting and short acting insulin
Modify insulun with Polypeptide OR adding a fatty acid chain
- Rapid = chnage the order of Pysine and proline residues OR add absorbic acid residuce —> chnages the charge/interactio time
- Long acting = tether to interstitial space by adding fatty acid or double lysine residues
Insulin Action on classically responsive tissues
Insulin acts on classicy responsive tissues –> binds to classic receptor on insulin respinsive tissues
- Example - Liver modultaes fats
When fed = increase nutritent = increase insulin = decrease catabolic porcess/increase anabolic process
- fed = synthesize glycogen (NOT making glucose)
- fed = modify fat stores glycogen and tiglycerides + NOT release substance
Decrease insuline = mobilize stored precursors
Insulin Action on Glucose uptake in Fat and Muscle
Insulin binds to insulin receptor –> recetor triggers many downstream chnages to promote Anobolic porcesses and make GLUT 4 go from inracelular pools to the membrane –> get glucose upatje (GLUT 4 takes in glucose)
Treating insulin relatd issues
List = shows diurgs that promote secretion of insulin (used for decades) – in the last 20/30 years = have diffreent kinds of drugs that can affect glucose metabolism in different ways –> NOW have meds that work on many pathways that regulate glucose metabolsim = have flexibility in treatmmet
NOTE - do NOT memorize drugs
Target organs and mechanism of Anti-diabetic drugs
Bone
Parathyroid regulates phosphate and calcium hmoeostasis
Parathyroid makes Parathyroid hormone (PTH) = regulates blood Calcium
Other organ endocrine function
Almost all organs have a “non-clasical” endcrine function - organs secrete substances in an endocrine fashion (have endorine aspects to tissues that are not thought to be classical)
Example:
1. Gut hormoans –> act as hormones but thought us settled of system they are acting
2. Heart secretings peptides to regulate action
3. Liver regulates body through IGF1
4. Placenta release peptides
Endothelial hormone signaling to otehr tissies crosses over to other settings
