Endocrine Lecture 1 Flashcards
Define the term homeostasis and how it relates to the endocrine system
Then explain “HYPER” and “HYPO”
Homeostasis: “the state of balance between opposing measures in the body with respect to various functions and to the chemical comp of fluids and tissues”
in terms of endocrine system: hormones are always there but always in balance:
HYPER: over production AND/OR hypersensitivity to hormonal effects
HYPO: underproduction of a hormone and or sensitivity to hormonal effects
Explain how integration works within the endocrine system
Integration:
There are two sets of effector systems around a set point
- coming from the nervous system itself
- coming from hormones
Chronic conditions can change the set point, and patients can get used to their new normal due to the changed set point
Endocrine pathologies:
-characterized by hormone _______ - ______ not _______
- Defect can be _______ or _______
- Symptoms can be vague and hard to diagnose: can overlap with other conditions or rare like weight loss, fatigue, hair loss, cognitive, dizzy
- Symptoms can take a long time to develop and might seem unrelated
Endocrine pathologies:
-characterized by a hormone imbalance - quantitative (not qualitative) change from normal
- Defect can be in classical endocrine gland (primary defect) or other organ (secondary/tertiary)
- Symptoms can be vague and hard to diagnose, overlap with other conditions or rare
- Symptoms can take a long time to develop and may seem unrelated
Provide an example of a congenital endocrine disease and explain it
Etiology: Congenital
Congenital Hypothyroidism (“cretinism”):
- Iodine defeciency during development
- Short stature/impaired bone formation
- mental retardation
- delayed motor development
Provide an example of a genetic endocrine disorder
(Etiology - genetic)
Etiology- Genetic:
Multiple Endocrine Neuroplasia (MEN)
- MEN 1, MEN 2A, MEN 2B
- characterized by 2-3 tumors in multiple endocrine glands
- all autosomal dominant (“all MEN think they are dominant)
- MEN 2B is only one tumor
Provide examples of the following etiologies for endocrine disorders:
1) Malignant tumors
2) Immunological Problems
3) Enviornmental Factors
Endocrine Disoder Etiologies:
1) Malignant Tumors: Small lung cell carcinoma
2) Autoimmune- T1DM (diabetes type 1)
3) Enviornmental Factors: PCBs, DES, birth control
Give examples for the following endocrine disorder etiologies:
1) Trauma/Stress
2) Surgical
3) Therapeutic
1) Trauma/Stress: Sheehan’s Syndrome: postpartum hemorrhage/shock; results in massive pituitary cell death
2) Surgical : thyroid gland removal
3) Therapeutic: glucocorticoid therapy (crohn’s disease)
Most Common Endocrine Pathology: T2DM
Diabetes Mellitus- Type 2 (T2DM):
- 1 in 10 people in the US have it
- 1 in 3 have “prediabetes”
- T2DM usually develops _______
- T2DM is highly correlated with ____
Most Common Endocrine Pathology: T2DM:
Diabetes Mellitus: Type 2 (T2DM)
- 1 in 10 people in the US have it
- 1 in 3 have prediabetes
- T2DM usually develops over a long period of time
- T2DM is highly correlated with obesity and BMI
Explain what “classical endocrine glands” are and list them for males and females
“Classical Endocrine Glands”:
- Classical endocrine glands are ductless (gland dumps hormone right into bloodstream or extracellular space without a ductal system)
The entire organ is dedicated to primarily endocrine function
Classical Endocrine Glands: Hypothalamus, Pituitary, Thyroid, Parathyroid, Adrenal, Pancreas, Ovaries, Testes
Explain non classical endocrine organs and list them and what they secrete
Non-Classical Endocrine Organs:
Specialized hormone secreting cells that are NOT in one of the glands
Brain - hypothalamus releasing hormones
Kidney - releases renin, Vitamin D, EPO
Heart: ANP and BNP
Liver: Insulin like growth factor (IGF1)
GI - serotonin and ghrelin
Adipose Tissue: leptin
Define modes of hormone release and transport to target sites:
autocrine
paracrine
endocrine
Autocrine: hormones secreted into interstitial space acting back on the same cell
Paracrine: hormones secreted into interstitial space and acting on a nearby cell
Endocrine: hormones secreted into the bloodstream to act on downstream target tissues
- note, because the targets are downstream, glands have to secrete a high concentration of hormones due to dilution effect
What are some factors effecting hormone bioavailability?
Factors affecting hormone bioavailability:
Hormone Transport : free vs bound, kinetics (half life and metabolism)
Target Tissues: receptors, chaperone proteins
Hormone synthesis/release: enzymatic activity, processing/packagin
Regulatory Mechanisms
Hormone Transport:
Hormone Binding Proteins:
Bind to hormones in blood to _____
Generally ____ the half life of the hormone
Mostly for _____ hormones
Also: which hormones?
Hormone Transport:
Hormone Binding Proteins:
Bind hormones in blood to facilitate transport
Generally increases the half-life of the hormone
Mostly for steroid hormones (lipophilic)
Also: IGF-1, GH, T4/T3
Explain the various binding proteins and what they bind to:
SHGB
CBG
TBG
TTR
Albumin
*Pak said to know these for the exam*
Highly Specific:
- SHBG (sex hormone binding globulin) binds to enstrogens and testosterone
- CBG- binds to cortisol/corticosterone
- TBG and TTR binds thyroid hormone
Nonspecific:
- Albumin - binds most lipophilic compounds in blood
Explain the concept of Free testosterone vs bioavailable testosterone
Free Testosterone is unbound testosterone in blood (not bound to anything)
Bioavailable testosterone = unbound + albumin bound
In men: 30-40% of testosterone is SHBG bound (not bioavailable), the rest is albumin bound, and a tiny bit of unbound/free testosterone
Women have 70% SHBG bound (not bioavailable) and 25% albumin bound
Explain the metabolic fate of hormones:
Hormones clearance can be through:
-
-
-
Metabolic Fate of Hormones:
Hormone Clearance can be through:
- intracellular metabolism
- liver metabolism
- urinary/fecal exretion
There can be intracellular metabolism, but generaly speaking hormones are metabolized by the liver. Liver: Phase I is reduced and hydroxylated, phase two is conjugation and then they get excreted via bile or urine
Describe how bound hormones are delivered to target cells
Scenario 1: scientists originally thought that steroid hormones are released at membrane, freely diffuses across lipid bilayer and then finds intracellular targets
NOW we understand that
Scenario 2:
- hormone/protein complex binds to megalin
- formation of endocytotic vesicle
- hormone dissociates and is released from vesicle
Now it is understood to have more specificity where megalin binds the hormone on the surface
Hormone Receptors:
- No receptor means no ___
- pharmalogical “block” :
- pharmalogical activation :
- Receptors determine the _____ of hormone activity
- cell surface receptors =
- intracellular receptors =
- _______ by ligand
* up/down regulation of receptors depends on _____
Hormone Receptors:
- No receptor = no action
- pharma block : antagonist
- pharma activator: agonist
- Receptors determine the duration of hormone activity
- cell surface receptors = internalization/dissociation
- intracellular receptors= ubiquination
- Autoregulation by ligand
* up and down regulation of receptors depends on hormone levels
Hormone Receptor Binding:
Explain the difference between specificity and affinity
Draw the graph explaining fraction of surface receptors bound with ligand and physiological response (what is the significance of this graph)
Hormones bind to receptors with high specificity and high affinity
Specificity: ability to distinguish between similar substances
Affinity: measured as Kd (Kd = ligand concentration that occupies 50% of binding sites, smaller number means higher affinity)
Graph shown in picture attached, significance is that at Kd the physiological response is 80%, meaning that for the endocrine system, you don’t need to bind very many receptors to get the full physiological response (Kd almost doesn’t matter)
Receptors for Lipophobic Hormones:
Lipophobic hormones bind to _____ receptors
Those receptors are coupled to _____
Then there is rapid internalization or degradation
Receptors for Lipophobic Hormones:
Lipophobic hormones bind to cell surface receptors
Those receptors are coupled to second messenger signaling pathways including: cAMP, IP3/DAG
Rapid internalization or degradation.
Hormones DO NOT bind to _______
Hormones do NOT bind to ion channel receptors
Lipophillic Hormones:
- Lipophillic hormones bind mainly to ______ receptors (with some exceptions)
- Often bound to large _________ in the cytoplasm
- Usually ______ biological response
- Can repress or activate transcription
Lipophillic Hormone Receptors:
- Lipophillic hormones bind mainly to intracellular receptors (with some exceptions)
- Lipophillic hormones are often bound to large chaperone proteins in the cytoplasm
- Usually SLOW biological response - requires transcription/translation events
- Can repress or activate transcription
Thyroid Hormone:
Thyroid hormones bind to _____ receptors
Transcription is ______ when the receptor is NOT bound to a ligand
Ligand (thyroid hormone) binding _____ gene transcription
Thyroid Hormone:
Thyroid Hormones bind nuclear receptors
Transcription repressed when receptor is NOT bound to ligand (apo-receptor)
Ligand (thyroid hormone) binding activates gene transcription
Chem Classification of Hormones- 3 Major Classes
- Amines (half life : ____)
- Catecholamines: derived from ___
- Indolamines: derived from ____
- Thyroid Hormone (T4/T3): derived from ___-
2. Peptides/Proteins (half life:____)
3. Steroids (half life:____)
Chemical Classification of Hormones:
- Amines (half life: 2-3 minutes)
- Catecholamines: derived from single tyrosine
- Indolamine: derived from single tryptophan
Thyroid Hormone (T4/T3) derived from 2 tyrosines (very long half life due to TBG, T4= 8 days, T3= 24 hours)
- Peptides/Proteins (half life 4-170 minutes), most hormones are of this type
- Steroids (half life is minutes to several hours)
Catecholamines & Indolamines:
- Half life is _____. These hormones act ____ and are ____ degraded
- Travel ____ in blood
- Always bind to the ______ receptor to activate ___
- Main difference between catecholamines and indolamines is ____. Explain
Catecholamines & Indolamines:
- Half life is very short. These hormones act very fast and are rapidly degraded.
- Travel freely in the blood
- Always bind to a cell surface receptor to activate second messenger signaling pathways
- Main difference between catecholamines and indolamines is synthesis. Catecholamines (tyrosine) and Indolamines (tryptophan). Therefore each is synthesized by tyrosine or tryptophan hydroxylase
CATECHOLAMINES: _______ derived
What are examples of catecholamines (there are three)
_______ is the rate limiting step. Often used as a marker for dopaminergic activity.
Draw out a few of the synthesis steps.
CATECHOLAMINES: Tyrosine- derived
- Dopamine, Norepinephrine, Epinephrine (aka noradrenaline and adrenaline)
- Tyrosine hydroxylase is the rate limiting step, often used as a marker for dopaminergic activity
Steps are outlined in the attached image. Tyrsosine——–> LDOPA (done by tyrosine hydroxylase) and then DOPA DCC synthesizes LDOPA—–> Dopamine
Then dopamine is turned into norepi and then finally epi
DOPAMINE:
Functions as an NT and a hormone
Dopamine is made in 2 main body organs:
1.
2.
WHat is the hormone action of dopamine?
Dopamine:
Functions as a NT and a hormone
Dopamine is made in 2 main body organs:
- Brain:
- substantia nigra (Parkinson’s Disease)
- Ventral Tegmental area
- Arcuate Nucleus (for release to pituitary)
Regulates multiple brain functions as an NT: reward pathways, attention, mood
- Adrenal Gland: adrenal medulla is where it is converted to NE
Hormone action: inhibits prolactin release from anterior pituitary
As a hormone, dopamine is sent from arcuate nucleus, to the anterior pituitary, where it blocks prolactin release
NOREPINEPHRINE:
Functions as an NT and a hormone
Requires ______ stimulation
Most tissue concentrations equal that of the synapse - meaning _____
_________ catalyzes the reaction
Norepinephrine:
Functions as a NT and as a hormone
Requires sympathetic NS stimulation
Most tissue concentrations equal that of the synapse - conversion takes place primarily in neurons
Dopamine Beta-hydroxylase catalyzes the reaction
SNS is stimulation is required to activate that enzyme.
All conversion happens in the neuron, very little NE in blood stream
Norepinephrine:
Sympathetic post-ganglionic neurons release NE
NE acts through both ___ and ____ adrenergic receptors
Splanchnic nerve innervates the _____ where conversion to epinephrine happens
_______ of ________ are homologoes to postsympathetic neurons - they release hormones into the blood
Norepinephrine:
Sympathetic post-ganglionic neurons release NE
NE acts through both alpha and beta adrenergic receptors
Splanchnic nerve innervates the adrenal medulla where convertion to epinephrine occurs
Chromaffin cells of adrenal medulla are homologous to postsympathetic neurons - release hormones into the blood
INDOLAMINES: _____ derived
_______ is the rate limiting enzyme
Explain what two hormones tryptophan can get turned into
Indolamines: tryptophan derived
Tryptophan hydroxylase (TPH) is rate limiting
Serotonin - both an NT and a hormone
Melatonin - hormone produced in pineal gland
Progression: tryptophan —–> 5HTP —–> serotonin—> —-> Melatonin
Serotonin: 5HT
is a _____ in the brain, called the “_______ hormone”
Most (95%) of serotonin in the body is produced by _______ cells - this is the endocrine action of serotonin:
- acts as vaso______
- stimulates smooth muscle _____ in intestine
Serotonin: 5-HT
Neurotransmitter in the brain: called the “happiness hormone:
Most (95%) of serotonin in the body is produced by enterochromaffin cells inthe gut - this is the “endocrine” action of serotonin
- vasoconstrictor
- stimulates smooth muscle contraction in intestine
SSRI’s: Selective Serotonin Reuptake Inhibitors
What do they do?
Used clinically to treat depression and other related mental health disorders
Clinical Considerations:
Physiological basis of depression not well understood
_______ of postsynpatic receptors
_______ feedback
SSRI’s: Selective Serotonin Reuptake Inhibitors:
Increases the concentration of serotonin at the synaptic cleft by blocking its reuptake
Used clinically to treat depression and other related mental health issues
Clinical Considerations:
Physiological basis of depression is not well understood
Desensitization/downregulation of postsynaptic receptors
Negative feedback - less serotonin produced in presynaptic cells
Melatonin Secretion:
- Melatonin is ONLY made in the ______ because it is sensitive to light
- Light information is conveyed to the SCN via the _______ tract
- The ____ trasmits the information to the _____ to regulate its circadian activity
- Melatonin is undetectable during ______ and peaks during _____
Melatonin Secretion:
Melatonin is only made at NIGHT because it is sensitive to light
- Light information is conveyed to the SCN (circadian clock) via the retinohypothalamic tract (RHT)
- The SCN trasmits the information to the pineal gland to regulate its circadian activity
-Melatonin is undetectable during daytime and peaks in the middle of the night
Melatonin:
- Converted from _____ in the pineal gland
_________ is the rate limiting enzyme and is the most active during the night
Used therapeutically for variety of conditions such as insomnia, jet lag, migranes
Potent inhibitor of reproduction - causes decreased _____ and _____ in males
Melatonin:
Converted from serotonin in the pineal gland
N-acetyltransferase is the rate limiting enzyme and is the most active during the night
Used therapeautically for a variety of conditions such as insomnia, jet lag, migraines, etc
Potent inhibitor of reproduction - causes decreased spermatogenesis and testis size in males
Monoamine Metabolism:
What are the two primary mechanisms of monoamine metabolism?
Explain which enzymes do each mechanism
Monoamine Metabolism:
Two primary mechanisms: Deamination and Methylation
- Deamination: Monoamine Oxidase (MAO) = oxidative deamination…. removes an enture amine group resulting in aldehyde intermediates….. inactivates catecholamines AND indolamines
Note; MAOIs are drugs that are used to treat depression and anxiety by increasing catecholamine and indolamine levels
- Methylation: COMT adds a methyl group… metabolism of catecholamines only (doesn’t work on indolamines at all)
Monoamine Deamination:
Explain Step 1 and Step 2
What is the primary metabolite for sympathetic nerves?
Monoamine Deamination:
Step 1: deamination by MAO to form aldehydes
Step 2: Aldehydes very short lived, converted to alcohol or acud metabolites by AD (aldehyde dehydrogenase) or AR (aldose reductase)
DHPG is a primary metabolite in sympathetic nerves – major pathway for catecholamine metabolism
DHPG is in the breakdown of NE (DHPG can be measured in urine to determine the levels of NE)
Catecholamine Methylation:
-COMT Methylation
Major source of metanephrine and normetanephrine in the _______
Converts _____ to ______
Catecholamine Methylation:
COMT Methylation:
- Major source of metanephrine and normetanephrine in the adrenal gland
- Converts DHPG to MHPG - precursor of VMA
VMA can be measured in urine to measure NE and EPi levels that someone has in their blood
VMA is a main indicator that someone has a tumor on adrenal gland producing WAY too much NE
Key Concepts: Catecholamine Metabolism:
- Majority of metabolism occurs in _____
- _____ is the major enzyme responsible for metabolism in neurons
- ____ is the major enzyme in the adrenal lgland and extraneural tissues
- Metabolites are excreted in urine
Note: COMT does not contribute to indolamine metabolism
Key Concepts: Catecholamine Metabolism:
- Majority of metabolism occurs in sympathetic nerves
- MAO is the major enzyme responsible for metabolism in neurons
- COMT is the major enzyme in the adrenal gland and extraneural tissue
- Metabolites are excreted in urine
Explain protein hormone processing
Transcription then splicing to get mRNA
All protein hormones are made this way:
5’ signal peptide + hormone + copeptides 3’
Signal is important to direct to ER
While the signal is still attached it is called a preprohormone
Prohormones: once the signal gets cut off and it is only hormones + copeptides
Then copeptides get cleaved and it becomes hormone
How long is the half life of most protein/peptide hormones?
What is the exception
Most protein hormones only last minutes, from a minute up to 30 minutes
The big exception is IGF-1 from the liver, which has a half life of 12-15 hours. This is due to TBG, the binding protein that keeps it super stable
Key Concepts for Steroid Hormones:
- Steroid hormones are derived from _____
- Steroid hormones are lipo-_____
- They are made in the ____, _____, ___ and ___
- There are five classes
- 21 carbon steroids:
- 19 carbon steroids
- 18 carbon steroids
Vitamin ___ is a secosteroid (means one of carbon rings is cleaved)
Key Concepts for Steroid Hormones:
- Steroid hormones are derived from cholesterol
- Steroid hormones are lipophillic
- They are made in placenta, adrenal gland, testes and ovaries (also skin makes vit D)
- There are five classes of steroid hormones
- 21 carbon steroids: glucocorticoids, mineralcorticoids, and progestins
- 19 carbon steroids: androgens
- 18 carbon steroids: estrogens
Vitamin D is a secosteroid (meaning one of the carbon rings is cleaved)
Explain how steroid hormones are made:
Cholesterol is transported from the ____ mitochondria to the ____ mitochondria by the protein called ____
Where the enzyme _____ converts it to _____
Synthesis of steroid hormones
Cholesterol is originally in the outer mitochondria, gets sent to inner mitochondria via STAR protein, where cholesterol then gets converted to pregnenolone via the enzyme desmolase/P450scc
List the four examples given by Pak as examples of positive feedback and explain them
Positive Feedback: childbirth, lactation, ovulation, blood clotting
- Parturition/Childbirth: contractions stimulate oxytocin release from the hypothalamus– more contraction stimulate more oxytocin–birth stops loop
- Lactation: suckling stimulates oxytocin release from hypothalamus–more suckling stimulates more oxytocin— lack of suckling stops loop
- Ovulation: LH stimulates estradiol —- estradiol stimulates more LH–release of oocyte stops the loop
- Blood Clotting: tissue injury activated plateles —platelets activate more platelets—clotting stops release of signals that activate platelets
Explain what an endocrine axis is
Endocrine Axis:
Three tiered biological system : hypothalamic neurons, anteriit pituitary cells, peripheral endocrine gland
Hormones can exert feedbac to regulate any part of axis
Important for diangnosing cause of endocrine disorder: primary endocrine disorder (peripheral gland), secondary endocrine disease (pituitary gland), tertiary endocrine disease (hypothalamus)
Hypothalamus is most upstream, then pituitary is intermediate, then peripheral gland is the target
Explain how hypothalamic hormones use negative feedback mechanisms:
Explain the concepts of short loop vs long loo
Hypothalamic hormones use negative feedback mechanisms:
“short loop”: hormone feedback from pituitary to hypothalamus
“long loop”: feedback from peripheral gland back tp pituitary or hypothalamus
Negative Feedback - Two major types
Explain the following negative feedback types:
- Physiological Response-Driven Negative Feedback
- Endocrine Axis-Driven Negative Feedback
Negative Feedback- Two Major Types
- Physiological Resonse driven negative feedback
This is where the physiological affect causes the negative feedback (example no more glucose in blood turning down insulin levels)
- Endocrine Axis driven negative feedback : the hormone itself causes negative feedback on the pituitary gland and the hypothalamus
What are the factors affecting circulating hormone levels:
1.
2.
3.
4.
5.
Factors Affecting Circulating Hormone Levels:
- Age
- Body Weight
- Time of Day
- Male/Female
- Diet
Explain how the levels of the following hormones change throughout one’s life: (think of the graph)
Catecholamines
Glucocorticoids
Testosterone
Estradiol
Adrenal Androgens
Atrial and Brain Natriuretic Peptides (ANPs and BNPs)
Made in the heart, regulates ______
BNP: ____ half life than ANP, making it useful for…
Normal levels can rule out _____
Higher levels are with _______
- Lower levels with ____
- _______ with age
-________ levels in women
ANPs and BNPs:
- Made in the heart, regulates blood pressure
BNP: longer half life than ANP, making it a useful diagnostic tool
Normal levels can rule out CHF
Higher levels with heart and renal failure
Lower levels with obesity
Increases with age
Higher levels in women
What are the rate limiting enzymes in the synthesis of the following:
- Catecholamines
- Indolamines
- Norepinephrine
- Melatonin
- Catecholamines: tyrosine hydroxylase
- Indolamines: tryptophan hydroxylase
- Norepinephrine: dopamine ß-hydroxylase (catalyzes rxn from dopamine —–> NE)
- Melatonin: N-acetyltransferase is rate limiting enzyme (most active during the night)
