Endocrinology 1 Flashcards
Describe the classical endocrine glands in both males and females and contrast with non-classical endocrine glands.
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
Describe the non-classical endocrine organs and what they release.
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
Define homeostasis as it relates to the endocrine system and explain how the endocrine system is integrated with other body systems.
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.
How are endocrine pathologies characterized?
Describe symptoms.
List primary sources of endocrine pathologies and provide examples in each category.
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”)
Provide an example for a congenital endocrine pathology.
Cretinism
Iodine deficiency during development
Short stature/impaired bone formation
Mental retardation
Delayed motor development
Provide an example for genetic endocrine pathology.
Multiple Endocrine Neoplasia (MEN)
characterized by 2-3 tumors in multiple endocrine glands
(parathyroid, pituitary, entero-pancreatic)
Provide an example for endocrine pathologies relating to malignant and benign tumors, infections/immunological problems and environmental factors .
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
Provide an example for endocrine pathologies relating to trauma/stress, surgical, or therapeutic.
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)
What is the most common endocrine pathology? What is the highest risk factor?
Diabetes mellitus – Type 2
obesity is highest risk factor
Define modes of hormone release and transport to target sites: autocrine, paracrine, endocrine.
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.
Discuss the concept of “bound” vs. “free” hormones: how do plasma binding proteins contribute to hormone stability and bioavailability?
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.
Compare/contrast the regulation of signaling between endocrine and paracrine.
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
Describe highly specific and non-specific hormone transport.
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
Is a hormone bound to albumin bioactive?
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
Describe how “bound” hormones are delivered to target cells.
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.
Describe how receptors could be blcoked or activated.
How do cell surface vs intracellular receptors determine duration of hormone activity.
Describe autoregulation by ligand.
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.
Describe action of antagonist vs agonist.
Pharmacological “block” (antagonist) Pharmacological activation (agonist)
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?
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.
Describe the Binding assays for estrogen related receptor (ERRγ) and ligand (4-OH tamoxifen).
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.
Describe lipophobic cell surface receptors.
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
Compare/contrast receptor linked kinases and receptor kinases.
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
Describe lipophilic hormone receptors.
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
Give an example of lipophilic hormone receptor.
Describe active/suppressed state.
Thyroid hormones bind nuclear receptors
When receptor is NOT bound to ligand = transcriptional repression
Ligand (thyroid hormone) binding activates gene transcription
What are the factors affecting hormone bioavailability?
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
