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Endocrine Lecture 1 Flashcards

1
Q

Define the term homeostasis and how it relates to the endocrine system

Then explain “HYPER” and “HYPO”

A

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

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2
Q

Explain how integration works within the endocrine system

A

Integration:

There are two sets of effector systems around a set point

  1. coming from the nervous system itself
  2. 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

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3
Q

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
A

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
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4
Q

Provide an example of a congenital endocrine disease and explain it

A

Etiology: Congenital

Congenital Hypothyroidism (“cretinism”):

  • Iodine defeciency during development
  • Short stature/impaired bone formation
  • mental retardation
  • delayed motor development
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5
Q

Provide an example of a genetic endocrine disorder

(Etiology - genetic)

A

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
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6
Q

Provide examples of the following etiologies for endocrine disorders:

1) Malignant tumors
2) Immunological Problems
3) Enviornmental Factors

A

Endocrine Disoder Etiologies:

1) Malignant Tumors: Small lung cell carcinoma
2) Autoimmune- T1DM (diabetes type 1)
3) Enviornmental Factors: PCBs, DES, birth control

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7
Q

Give examples for the following endocrine disorder etiologies:

1) Trauma/Stress
2) Surgical
3) Therapeutic

A

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)

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8
Q

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 ____
A

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
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9
Q

Explain what “classical endocrine glands” are and list them for males and females

A

“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

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10
Q

Explain non classical endocrine organs and list them and what they secrete

A

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

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11
Q

Define modes of hormone release and transport to target sites:

autocrine

paracrine

endocrine

A

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
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12
Q

What are some factors effecting hormone bioavailability?

A

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

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13
Q

Hormone Transport:

Hormone Binding Proteins:

Bind to hormones in blood to _____

Generally ____ the half life of the hormone

Mostly for _____ hormones

Also: which hormones?

A

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

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14
Q

Explain the various binding proteins and what they bind to:

SHGB

CBG

TBG

TTR

Albumin

A

*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
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15
Q

Explain the concept of Free testosterone vs bioavailable testosterone

A

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

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16
Q

Explain the metabolic fate of hormones:
Hormones clearance can be through:

-

-

-

A

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

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17
Q

Describe how bound hormones are delivered to target cells

A

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

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18
Q

Hormone Receptors:

  1. No receptor means no ___
  • pharmalogical “block” :
  • pharmalogical activation :
  1. Receptors determine the _____ of hormone activity
  • cell surface receptors =
  • intracellular receptors =
  1. _______ by ligand
    * up/down regulation of receptors depends on _____
A

Hormone Receptors:

  1. No receptor = no action
  • pharma block : antagonist
  • pharma activator: agonist
  1. Receptors determine the duration of hormone activity
  • cell surface receptors = internalization/dissociation
  • intracellular receptors= ubiquination
  1. Autoregulation by ligand
    * up and down regulation of receptors depends on hormone levels
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19
Q

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)

A

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)

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20
Q

Receptors for Lipophobic Hormones:

Lipophobic hormones bind to _____ receptors

Those receptors are coupled to _____

Then there is rapid internalization or degradation

A

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.

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21
Q

Hormones DO NOT bind to _______

A

Hormones do NOT bind to ion channel receptors

22
Q

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
A

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
23
Q

Thyroid Hormone:

Thyroid hormones bind to _____ receptors

Transcription is ______ when the receptor is NOT bound to a ligand

Ligand (thyroid hormone) binding _____ gene transcription

A

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

24
Q

Chem Classification of Hormones- 3 Major Classes

  1. Amines (half life : ____)
  • Catecholamines: derived from ___
  • Indolamines: derived from ____
  • Thyroid Hormone (T4/T3): derived from ___-
    2. Peptides/Proteins (half life:____)
    3. Steroids (half life:____)
A

Chemical Classification of Hormones:

  1. 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)

  1. Peptides/Proteins (half life 4-170 minutes), most hormones are of this type
  2. Steroids (half life is minutes to several hours)
25
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
26
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
27
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: 1. _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 2. _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
28
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
29
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
30
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
31
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
32
_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
33
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
34
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
35
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 1. 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 2. Methylation: **COMT** adds a methyl group... metabolism of catecholamines only (doesn't work on indolamines at all)
36
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)
37
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
38
Key Concepts: Catecholamine Metabolism: 1. Majority of metabolism occurs in \_\_\_\_\_ 2. _____ is the major enzyme responsible for metabolism in neurons 3. ____ is the major enzyme in the adrenal lgland and extraneural tissues 4. Metabolites are excreted in urine Note: COMT does not contribute to indolamine metabolism
Key Concepts: Catecholamine Metabolism: 1. Majority of metabolism occurs in sympathetic nerves 2. MAO is the major enzyme responsible for metabolism in neurons 3. COMT is the major enzyme in the adrenal gland and extraneural tissue 4. Metabolites are excreted in urine
39
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
40
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
41
Key Concepts for Steroid Hormones: 1. Steroid hormones are derived from \_\_\_\_\_ 2. Steroid hormones are lipo-\_\_\_\_\_ 3. They are made in the \_\_\_\_, \_\_\_\_\_, ___ and \_\_\_ 4. 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: 1. Steroid hormones are derived from cholesterol 2. Steroid hormones are lipophillic 3. They are made in placenta, adrenal gland, testes and ovaries (also skin makes vit D) 4. 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)
42
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
43
List the four examples given by Pak as examples of positive feedback and explain them
Positive Feedback: childbirth, lactation, ovulation, blood clotting 1. **Parturition/Childbirth**: contractions stimulate oxytocin release from the hypothalamus-- more contraction stimulate more oxytocin--birth stops loop 2. **Lactation**: suckling stimulates oxytocin release from hypothalamus--more suckling stimulates more oxytocin--- lack of suckling stops loop 3. **Ovulation**: LH stimulates estradiol ---- estradiol stimulates more LH--release of oocyte stops the loop 4. **Blood Clotting**: tissue injury activated plateles ---platelets activate more platelets---clotting stops release of signals that activate platelets
44
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
45
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
46
Negative Feedback - Two major types Explain the following negative feedback types: 1. Physiological Response-Driven Negative Feedback 2. Endocrine Axis-Driven Negative Feedback
Negative Feedback- Two Major Types 1. 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) 2. Endocrine Axis driven negative feedback : the hormone itself causes negative feedback on the pituitary gland and the hypothalamus
47
What are the factors affecting circulating hormone levels: 1. 2. 3. 4. 5.
Factors Affecting Circulating Hormone Levels: 1. Age 2. Body Weight 3. Time of Day 4. Male/Female 5. Diet
48
Explain how the levels of the following hormones change throughout one's life: (think of the graph) Catecholamines Glucocorticoids Testosterone Estradiol Adrenal Androgens
49
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
50
What are the rate limiting enzymes in the synthesis of the following: 1. Catecholamines 2. Indolamines 3. Norepinephrine 4. Melatonin
1. Catecholamines: **tyrosine hydroxylase** 2. Indolamines: **tryptophan hydroxylase** 3. Norepinephrine: **dopamine ß-hydroxylase** (catalyzes rxn from dopamine -----\> NE) 4. Melatonin: **N-acetyltransferase** is rate limiting enzyme (most active during the night)

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