Endocrinology 1

Question 1

Describe the classical endocrine glands in both males and females and contrast with non-classical endocrine glands.

Answer 1

Classical endocrine glands are ductless.

Secrete hormones directly into the bloodstream or extracellular space

The organ is dedicated primarily to endocrine function

Classical: pineal gland, pituitary gland, thyroid gland, parathyroid gland, adrenal gland, endocrine pancreas, ovaries and testes

Non-classical endocrine organs: 
Brain 
Kidney
Heart 
Liver 
GI

Adipose Tissue - leptin

Question 2

Describe the non-classical endocrine organs and what they release.

Answer 2

Brain – especially hypothalamus (“releasing hormones”)

Kidney – Renin, Vitamin D, erythropoietin (EPO)

Heart – atrial/brain natriuretic peptide (ANP, BNP)

Liver – Insulin-like growth factor
(IGF-I)

GI – small intestine, stomach (serotonin, ghrelin)

Adipose Tissue - leptin

Question 3

Define homeostasis as it relates to the endocrine system and explain how the endocrine system is integrated with other body systems.

Answer 3

HYPER = overproduction of a hormone and/or hypersensitivity to hormonal effects

HYPO = underproduction of a hormone and/or insensitivity to hormonal effects.

see slide 15 - effect on thymus

Hormone itself not doing the action has to be receptor at target tissue that accepts hormone and that RECEPTOR is what initiates downstream signaling.
Over prod. of hormone, could bind to receptor it normally wouldn’t bind to… now all functions you normally associate w that receptor will be activated (adrenal gland and pathologies associated w that…)

The brain senses both external and internal cues, which subsequently
activates multiple components of the endocrine system. The response can be inhibitory or stimulatory at the same target cell in order to achieve equilibrium. The target cell response to
hormone depends on the ratio of the receptors present in the cell.

Question 4

How are endocrine pathologies characterized?
Describe symptoms.

List primary sources of endocrine pathologies and provide examples in each category.

Answer 4

Characterized by a hormone imbalance – (hypo- or hyper-secretion of hormone)
Defect can be in endocrine gland (primary defect) or other organ

Symptoms can be vague and hard to diagnose
Weight/Appetite changes
Fatigue
Hair loss/Hirsutism
Cognitive (forgetfulness/confusion)
Dizziness
Moodiness (depression/anxiety/aggression)
Symptoms can take a long time to develop and might seem unrelated

Etiologies
Congenital (“cretinism”)
Genetic (congenital adrenal hyperplasia (CAH), multiple endocrine neoplasia (MEN))
Trauma/Stress (Sheehan’s syndrome)
Surgical (thyroidectomy)
Therapeutic (glucocorticoid therapy)
Malignant and benign tumors (neoplastic tissues, small lung cell carcinoma)
Infections/immunological problems
Autoimmune (Diabetes Mellitus Type 1)
Environmental Factors (“endocrine disruptors”)

Question 5

Provide an example for a congenital endocrine pathology.

Answer 5

Cretinism

Iodine deficiency during development
Short stature/impaired bone formation
Mental retardation
Delayed motor development

Question 6

Provide an example for genetic endocrine pathology.

Answer 6

Multiple Endocrine Neoplasia (MEN)
characterized by 2-3 tumors in multiple endocrine glands
(parathyroid, pituitary, entero-pancreatic)

Question 7

Provide an example for endocrine pathologies relating to malignant and benign tumors, infections/immunological problems and environmental factors .

Answer 7

Malignant and benign tumors:
Neoplastic tissues
Small lung cell carcinoma

Infections/immunological problems
Autoimmune – Diabetes Mellitus Type 1

Environmental Factors (“endocrine disruptors”)
PCBs, DES, birth control

Question 8

Provide an example for endocrine pathologies relating to trauma/stress, surgical, or therapeutic.

Answer 8

Trauma/Stress
Sheehan’s Syndrome – postpartum hemorrhage/shock; results in massive pituitary cell death

Surgical
Thyroid gland removal (often parathyroid injury)

Therapeutic
Glucocorticoid therapy (Crohn’s disease and others)

Question 9

What is the most common endocrine pathology? What is the highest risk factor?

Answer 9

Diabetes mellitus – Type 2

obesity is highest risk factor

Question 10

Define modes of hormone release and transport to target sites: autocrine, paracrine, endocrine.

Answer 10

Endocrine – hormones secreted into the blood acting on downstream target tissues.

Paracrine – hormones secreted into the interstitial space acting at nearby cells.

Autocrine – hormones secreted into the interstitial space acting back on same cell.

Slide 31

Paracrine actions are
on neighboring cells.
Neurotransmitter
transmission between
neurons is also a type
of paracrine signaling. For endocrine action the
hormone must travel
through the blood to
reach its target cell.

Question 11

Discuss the concept of “bound” vs. “free” hormones: how do plasma binding proteins contribute to hormone stability and bioavailability?

Answer 11

Hormone Binding Proteins
-Bind to hormones in blood to facilitate transport
-Generally increases the half-life of the hormone
-Mostly for steroid hormones (lipophilic)
Also: IGF-I, GH, T4/T3

Important Concept: “free” vs. “bound” hormones. Only “free” hormones are biologically active

Hormone Transport - most lipophilic hormones are
bound to other proteins in the blood. Amines and
peptides usually circulate freely.

Question 12

Compare/contrast the regulation of signaling between endocrine and paracrine.

Answer 12

Endocrine:
source: no contribution to specificity of target, synthesis/secretion

Distribution: blood stream

• universal-almost
• importance of dilution

Non-target organ (metabolism) or target cell:
-receptor is source of specificity
Responsiveness:
-number of receptors
-downstream pathways
-other ligands
-metabolism of ligand/receptor
-all often regulated by ligand 

Paracrine:
Source is adjacent cell:
-major determinant of target
-synthesis/secretion

Target cell:
Receptor- specificity and sensitivity, diffsuion barrier, determinant of gradient

induced inhibitor pathways, ligands, and binding proteins

Distribution: matrix:

• diffusion distance
• binding proteins: BMP, IGF
• proteases
• matrix components

Slide 32

Question 13

Describe highly specific and non-specific hormone transport.

Answer 13

Highly specific:
Sex hormone binding globulin (SHBG) – binds estrogens and testosterone

Corticosteriod binding globulin (CBG) – binds cortisol/corticosterone

Thyroxine binding globulin (TBG) and transthyretin (TTR) – binds thyroid hormone

Non-specific:
Albumin – binds most lipophilic compounds in blood

Highly specific-specific for one particular hormone and always want to find that hormone.

If don’t have specific one, then almost everything else gets bind to albumin. if bound to highly specific then it will be a bit harder to get it off of there. dissociation needs signal
if bound to albumin-dissociation happens more easily

Question 14

Is a hormone bound to albumin bioactive?

Answer 14

stuff bound to albumin is bioavailable but not bioactive (can’t do anything while bound to albumin) but available to get hormone to dissociate from albumin when you need it

Question 15

Describe how “bound” hormones are delivered to target cells.

Answer 15

Slide 38
Scenario #1 –
Steroid hormone is released at membrane.
Freely diffuses across lipid bilayer.
Finds intracellular targets.

Scenario #2 –
Hormone/protein complex binds to megalin.
Formation of endocytic vesicle.
Hormone dissociates and is released from vesicle.

Question 16

Describe how receptors could be blcoked or activated.

How do cell surface vs intracellular receptors determine duration of hormone activity.

Describe autoregulation by ligand.

Answer 16

No receptor = no action
Pharmacological “block” (antagonist)
Pharmacological activation (agonist)

Determines duration of hormone activity
Cell surface receptors = internalization/dissociation
Intracellular receptors = ubiquitination

Autoregulation by ligand
Up/down regulation depending on hormone levels

Intracellular receptors subject to ubiquination once bound to ligand.
dep. on level of hormones receptors increased or decreased…dep. on transcriptional level.

Question 17

Describe action of antagonist vs agonist.

Answer 17

Pharmacological “block” (antagonist)
Pharmacological activation (agonist)

Question 18

Describe how hormones bind to receptors. Define both terms. Distinguish between hormone receptor affinity and specificity.

Graph relative concentration of ligand against fraction of maximal binding or cellular response. How does physiological response compare to fraction of surface receptors bound?

Answer 18

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
Ki = Ability to displace ligand at 50% of maximum activity
Smaller number = higher affinity

def. Kd as amount of ligand you need to occupy 50% of binding sites

Graph slide 41

have lots of receptors we refer to as high affinity low capacity- look at 50% mark then blue line (thats physiological response to horome…happened way before Kd) needed v little hormone to elicit 50% response. if go all way to 1 Kd can see more than 80% of physiological response by only binding half of receptors. don’t need much ligand and don’t need it to bind all the receptors to get a full physiological response

Note: ligand concentration for maximal physiological response does not necessarily correlate with the Kd.

Question 19

Describe the Binding assays for estrogen related receptor (ERRγ) and ligand (4-OH tamoxifen).

Answer 19

Slide 42
p 8 h/o
A radioligand binding assay for ERRγ. (A) Saturation binding curve of [3H]4-OHT and GST-ERRγ.
The graph shows total (●), specific (○), and nonspecific (■) binding. Excess unlabeled 4-OHT (30 μM) was used to determine nonspecific binding. The Kd of 4-OHT was 35 nM. (B) Nonradioactive
DES, TAM, and 4-OHT compete with [3H]4-OHT for binding to ERRγ. The Ki value for DES and
TAM was 870 nM; for 4-OHT the Ki was 75 nM.

Question 20

Describe lipophobic cell surface receptors.

Answer 20

LIPOPHOBIC

• Bind to cell surface receptors
• Coupled to second messenger signaling pathways including: cAMP, IP3/DAG
• Rapid internalization or degradation

can’t really get in so bind receptors on surface
diff kinds of receptors can be on surface- all have diff. intracellular signaling pathways they will activate
once ligand bound, these tend to be rapidly internalized and degraded
new receptors must be made or trafficked back to membrane

Slide 45-48
Class 1: Ion Channels
-Ligand binding causes conformational change that opens channel
-Neurotransmitters typically activate these types of receptors

Class 2: G protein-coupled
Most proteins and peptide hormones bind this class of receptor
Ligand binding activates second messenger signaling cascades

Class 3: Receptor-linked kinases - DO NOT have intrinsic catalytic activity.

• Ligand binding causes dimer formation – activates intracellular kinase
• Examples: Growth hormone (GH), prolactin, erythropoietin

Class 4: Receptor Kinases
Have intrinsic catalytic activity that is stimulated by ligand binding
Insulin and atrial natriuretic peptide bind to this type of receptor

Question 21

Compare/contrast receptor linked kinases and receptor kinases.

Answer 21

Class 3: Receptor-linked kinases - DO NOT have intrinsic catalytic activity.

• Ligand binding causes dimer formation – activates intracellular kinase
• Examples: Growth hormone (GH), prolactin, erythropoietin

Class 4: Receptor Kinases
Have intrinsic catalytic activity that is stimulated by ligand binding
Insulin and atrial natriuretic peptide bind to this type of receptor

Question 22

Describe lipophilic hormone receptors.

Answer 22

LIPOPHILIC
Bind mainly to intracellular receptors (with some exceptions).

Often bound to large chaperone proteins in cytoplasm (heat shock).

Usually SLOW biological response – requires transcription/translation events.

Can repress or activate transcription.

can diffuse across or be transported in..these receptors when in apostate (not bound to anything) tend to be associated w other proteins (chaperone proteins)… once ligand binds to it, those dissociate and usually that whole complex will translocate into nucleus

most are transcription factor so have slower biological response bc req. transcription and translation to occur
MUCH slower than membrane associated ones

doesn’t always stimulate, can also suppress

Question 23

Give an example of lipophilic hormone receptor.

Describe active/suppressed state.

Answer 23

Thyroid hormones bind nuclear receptors

When receptor is NOT bound to ligand = transcriptional repression

Ligand (thyroid hormone) binding activates gene transcription

Question 24

What are the factors affecting hormone bioavailability?

Answer 24

Factors affecting hormone bioavailability:

Hormone Transport:
Binding proteins – “free” vs bound
Kinetics: half-life

Target Tissues:
Receptors – mutations, desensitization, down/upregulation,
Chaperone/Heat shock proteins

Hormone synthesis/release:
Enzymatic activity
Processing/Packaging

Regulatory mechanisms:
Feedback
Circadian rhythms
Aging
Pulsatility
Metabolism/Degradation

Question 25

Give 3 examples of Receptor-linked kinases.

What binds to receptor kinases?

Answer 25

Growth hormone (GH), prolactin, erythropoietin

Insulin and atrial natriuretic peptide bind to this type of receptor