Endocrine Flashcards
Specificity vs. Affinity in Hormone Receptor Binding
SPECIFICITY: ability to distinguish between similar substances (at what [ ] must the substance be before the receptor is activated)
AFFINITY:
determined by Kd –> ligand [ ] that occupies 50% of binding sites (smaller Kd = higher affinity). ‘
Ki is also associated –> [ ] that a hormone must be at before it kicks off 50% of another ligand
Rate limiting step of catecholamine formation
Tyrosine Hydroxylase conversion of Tyrosine to XDOPA
Function of Dopamine
Tonic Inhibitor of prolactin release from anterior pituitary
Defining component of Catecholamines and the main type(s).
Derived from single tyrosine
-Dopamine, Epi, NE
Defining component of Indoleamines and the main type(s)
Derived from single tryptophan
-Serotonin is the main one (and melatonin comes from serotonin)
Rate limiting step of indoleamine formation
Tryptophan hydroxylase conversion of Tryptophan to an intermediate
Function of serotonin and where it is made.
95% made in gut. Acts as a vasoconstrictor and stimulates smooth muscle cell contraction in intestine.
Melatonin (formation, uses and consequences)
Formation: converted from serotonin in the pineal; N-acetyltransferase is the RLS
Function: Regulation of day and night cycles. Used therapeutically for variety of conditions including insomnia, jet lag, SAD, migraines, etc. Active only during night.
Potent inhibitor of male reproductive functions
Basics of biosynthetic processing of steroid hormones
StAR protein transports free cholesterol from outer to inner mitochondria where it is converted to pregnenolone by cytochrome P450scc desmolase. Pregnenolone is subsequently converted to the glucocorticoids, mineralcorticoids, androgens and estrogens.
PVN
Paraventricular Nucleus
CRH, TRH (anterior pit); AVP, OXY (posterior pit)
Thirst, BP, mood/emotion/stress
POA
Preoptic Nucleus
GnRH
Reproduction
ARC
Arcuate Nucleus
Growth Hormone Releasing Hormone (GHRH)
Feeding behavior, satiety
SCN
Suprachiasmatic Nucleus
Sleep, Circadian Rhythms
ME
Medial Eminence
Functional converging point for neurons of hypothalamus, where they all release their hormones
GnRH pulsatility every 30 -60 mins favors…
every 2-3hrs…?
30-60mins: LH
2-3hrs: FSH
Tuberoinfundibular System
Anterior Pituitary
Comprises all neurons that send axonal projections to the median eminence. Hormones target the anterior pituitary through the capillary system (endocrine).
Neurohypophysial Tract
Posterior Pituitary
Comprises neurons whose axons terminate in the posterior pituitary.
Major cell types of the anterior pituitary and what they secrete.
ACIDOPHILS (most abundant):
Somatotrophs (GH)
Lactotrophs (prolactin)
BASOPHILS:
Corticotrophs (ACTH)
Gonadotrophs (LH/FSH)
Thyrotrophs (TSH)
What composes 90% of the Anterior Pituitary?
Pars distalis
Herring Bodies
Dilations of unmyelinated axons near the terminals which serve as the site of hormone release for the POSTERIOR PITUITARY.
Prolactin vs Oxytocin
Prolactin: Milk production, mammory gland development and breast differentiation
Oxytocin: Milk ejection
Carrier for AVP? For Oxytocin?
AVP- neurophysin II
Oxy- neurophysin I
ADH is secreted from what cells?
Magnocellular (posterior pit): fluid balance
Paracellular (median eminence): stress/anxiety
Both are cells of the PVN
What does AVP bind to?
V1 RECEPTORS: vascular smooth muscle cells, producing contraction and increased vascular resistance
V2 RECEPTORS: distal collecting duct for AQP2 channel insertion and formation
Specific cell for release of oxytocin
Magnocellular neurons whose cells are located in PVN
Somatostatin
Inhibits pulsatile frequency of GHRH and thus blocks GH and TSH release from pituitary.
Also suppresses insulin release
GH Direct effects vs IGF-1 effects
GH Direct: (1) promotes lean body mass (increased protein and decreases adiposity). (2) Increases plasma glucose levels.
IGF-1 (GH Indirect): stimulates cellular proliferation in visceral organs and bone/cartilage growth. INSULIN DEPENDENT
Gigantism vs. Acromegaly
Both caused by GH Excess
GIGANTISM: GH excess before closing of epiphyseal plate in childhood. Increases long bone growth resulting in extreme height.
ACROMEGALY: Usually diagnosed in middle age and most often caused by pituitary adenoma. Gradual enlargement of hands/feet. Widening of face, protruding jaw, enlarged lips, tongue, nose and brow.
Types of Dwarfism
Both are GH deficiencies first established in childhood.
LARON SYNDROME: GH receptor doesn’t work (genetic defect). (1) no production of IGF-1 (2) Plasma levels are normal to high (loss of feedback)
AFRICAN PYGMY: partial defect in GH receptor so no pubertal increase in IGF-1. not noticed until puberty so tough to reverse. Normal plasma GH
Adult GH deficiency
(1) Caused by tumor/surgery or treatment
(2) increased fat deposition
(3) reduced bone density
(4) High LDL/TGs
Prolactin stimulation
Mainly by TRH (Thyrotropin-releasing hormone) and also oxytocin
Produced by hypothalamus to stimulate release of TSH and prolactin from anterior pituitary.
Prolactin inhibits release of what hormone?
GnRH –> which is why breast feeding moms don’t easily get pregnant.
CRH binds with highest affinity to what receptor?
CRH R1 in anterior pituitary to activate G-protein induced PKA pathway
What two hormones act synergistically to increase amplitude of ACTH release from the anterior pituitary?
- AVP
- CRH
Preprohormone of ACTH
POMC gene
Main ACTH action in adrenal gland
Stimulate biosynthesis of glucocorticoids
ACTH receptor
MC2R –> high affinity
MC1R –> low affinity (found in skin, causes hyper-pigmentation with high levels of ACTH)
Adrenal gland secretions by layer
Z. GLOMERULOSA: mineralocorticoids
Z. FASCICULATA: glucorticoids (cortisol)
Z. RETICULARIS: weak androgens (DHEA)
MEDULLA: catecholamines
Cortisol transport
CBG (corticosteroid binding globulin). Used to transport 90% of circulating cortisol in the blood.
Decreased by estrogen or shock/severe infection
Enzyme that converts cortisone to cortisol and what happens next
11B-HSD-1; Cortisol binds to intracellular GR receptor (after displacement of chaperone on GRR). This complex enters cell for transcription purposes.
Functions of Cortisol
I Got Caught With A Fancy B.M.W.
I: immunity/inflammation (Decreased) G: Glucose (Increase) C: Connective Tissue (Decrease) W: Water clearance and GFR (Increase) A: Arteriole tone (Increase) F: Fetal maturation (Increased) B: Bone (degradation) M: Muscle Mass (decrease) W: Wakefulness and emotional state
How does Cortisol increase muscle breakdown
FoxO transcription factor regulation which stimulates expression of E3 ubiquitin ligase and MuRF-1 which lead to protein degradation.
How does Cortisol increase fat breakdown and redistribution
MAG lipase and Hormone sensitive lipase (HSL)
How does Cortisol block immune function and nflammatory action?
- stimulates anti-inflammatory cytokines
- inhibits prostaglandins
- suppresses antibody production
- increases neutrophils, platelets and RBCs but blocks their function
- stimulates IkB (which binds NFkB) and binds directly to block NFkB
Cushing disease vs syndrome
What are their effects?
DISEASE: Excessive cortisol secretion due to pituitary adenoma
SYNDROME: Any other reason for excessive cortisol secretion
EFFECTS:
- purple stria
- change in body fat distribution (moon face, skinny arms, large abdomen)
- osteoporosis
- hypertension
- glucose intolerance
Addison’s disease
Autoimmune destruction of adrenals
Mineralocorticoids
Hormones that promote sodium retention by the kidney. Water retention = secondary result.
ALDOSTERONE –> main mineralocorticoid
Aldosterone main function/targets
Stimulate sodium and water reabsorption in the kidney; increases potassium secretion.
Mineralocorticoid Receptor is highly expressed in following:
- Kidney (distal tubule)
- Colon
- Salivary ducts
- Sweat ducts
Activation and inactivation of cortisol
inactivated to cortisone by 11B-HSD2 (occurs in MR. flows freely back into the blood)
Activated by 11B-HSD1 (can be used by GR)
Licorice and sodium/water retention
Increased licorice = inhibition of 11B-HSD2 = increased cortisol levels = cortisol activation of MR = increased sodium and water retention
DHEA
Precursor for testosterone and estrogens
Universal first step of steroid hormone biosynthesis
Conversion of cholesterol to pregnenolone via CYP11A1 side-chain removal
Congenital Adrenal Hyperplasia
Loss of ability to make certain vital hormones, often cortisol.
Caused by:
(1) 21-a hydroxylase deficiency: excess DHEA, no mineralocorticoids or glucocorticoids
(2) 11-B hydroxylase deficiency: salt and water retention due to excess in mineralocorticoids
Major cell type of the adrenal medulla and what causes its secretions
Chromaffin cells.
Stimulated to secrete catecholamines via spinal cord
Function of cortisol on NE
Cortisol stimulates conversion of NE to Epi, in the adrenal medulla
What works to degrade catecholamines?
COMT and MAO
Metabolic by-product of catecholamine degradation and its use.
Vanillymandelic acid (VMA)– secreted in urine and can be used clinically to detect tumors producing excess EPI or NE.
Pheochromocytoma
tumor originating from chromaffin cells, causing overproduction of catecholamines
Also known as “The 10% Tumor”:
10% of these tumors are…
malignant, bilateral, in children, familial, recurring, associated with endocrine tumors, present with stroke or are extra-adrenal
Main cellular components of thyroid
FOLLICLE:
- epithelial cells surrounding lumen
- lumen filled with colloid; major component is T3/T4 and thyroglobulin
PARAFOLLICULAR CELLS (“C” CELLS):
- produce calcitonin
- no contact with the colloid
OTHER:
-epithelial cells, fibroblasts, lymphocytes, adipocytes
Two precursors needed for thyroid hormone formation
Thyroglobulin (TG) and iodide
Minimum iodide intake for thyroid deficiency
20 ug/day (400 ug/day is average in U.S.)
Wolf-Chaikoff effect
Assures constancy of iodide storage in face of changes in dietary iodide.
Increases in iodide intake decrease gland transport and hormone synthesis. Clinically, very high iodide doses –> rapid thyroid shutdown.
Type I deiodinase
Type II deiodinase
Type III deiodinase
All convert T4 to T3 (or rT3)
I: primary source of T3 in circulation. liver, kidney, thyroid, skeletal.
II (MOST CRITICAL): peripherally deiodinates T4 to T3 in brain, pituitary, placenta and in the heart. Also acts as a THYROID HORMONE SENSOR.
III: only makes reverse T3 (no biological activity)
Inhibition of TSH release
Negative feedback of T3. Also Dopamine and somatostatin function tonically inhibit TSH function.
Steps of Thyroid Hormone Synthesis
(1) Iodide trapping
(2) Transport- Iodide transported to lumen and oxidized to iodine. Thyroglobulin transported to lumen
(3) Iodination of MIT/DIT onto thyroglobulin
(4) Conjugation to for T3/T4
(5) Endocytosis
(6) Proteolysis to release everything from vesicle
(7) secretion of T3/T4
Carbimazole (methimazole)
Inhibits thyroid peroxidase. Used as treatment for hyperthyroidism because iodide can no longer become iodine
NIS
Sodium iodide symporter which brings iodide into thyroid
Cold vs Hot spot
Seen during thyroid autoradiographs.
Cold = white spot surrounded by black = cancer Hot= black spot surrounded by white = hyperthyroidism
Organification defect
Iodide cannot be incorporated into tyrosine
THR
Thyroid hormone receptor
Internal. Member of the nuclear receptor superfamily. Heterodimerizes with retinoic acid receptor (RXR) upon ligand binding and then this THR:RXR complex assists in transcriptional activation.
Almost every cell type has THR
T3 and the CNS
T3 is critical for normal brain development.
- neuronal cell migration/differentiation
- myelination
- synaptic transmission
Grave’s disease
Hyperthyroid
Autoimmune antibodies stimulate TSH via Long-acting thyroid stimulator (LATS)
Elevated T3/T4
Hashimoto’s Thyroiditis
Hypothyroid
Autoimmune destruction of thyroid follicles.
Antibodies against TPO (thyroid peroxidase) , TG (thyroglobulin)
Thyroid Storm + treatment
Hyperthyroid coupled with severe acute illness
Could cause altered mental status and severe circulatory collapse leading to death.
TREATMENT: only acute treatment = PTU; carbimazole; beta blockers for heart function
What cells secrete PTH
The chief cells of the parathyroid gland
Osteoclasts and PTH
KEY CONCEPT
Osteoclasts do not have any receptors for PTH so stimulation is indirect. PTH stimulate macrophage colony-stimulating factor (M-CSF) in osteoblasts, which stimulates differentiation of osteoclast precursors.
PTH also stimulates RANK-L which leads to maturation of osteoclast and bone reabsorption.
OPG
Osteoprotegrin
Antagonist of RANK-L (and therefore is anti-bone breakdown). Works as RANK-L receptor decoy.
Stimulated by estrogens; inhibited by glucocorticoids
Function of PTH in Kidney
(1) stimulates Ca2+ reabsorption
(2) reduces phosphate reabsorption
(3) stimulates conversion of active form of Vit D via stimulation of CYP1a gene transcription
PTH Regulation
(1) Calcium-sensing receptor (CaSR). Binds ionized Ca2+. Inhibits PTH synthesis/stimulates its degradation. Located in PT chief cells, kidney tubules and C cells.
(2) Vit D. Inhibits PTH synthesis and stimulates CaSR.
Calciferol
General term for Vit D
Calcidiol
Aka Calcifidiol or 25-hydroxyvitamin D. Immediate precursor to active Vit D.
Formed in liver.
Calcitriol
Aka calcifitriol or 1, 25-dihydroxyvitamin D. Active form of Vit D.
1a-hydroxylase is the key enzyme for its formation
Formed in kidneys.
Vit D functions
- Some mobilization of Ca2+ from bone/ bone proliferation and differentiation.
- Increases Ca2+ (via TRPV5/6, calbindin and a Ca2+ ATPase pump for the Ca2+ reabsorption) and phosphate (via Na+-Pi cotransporter)
Primary vs Secondary Hyperparathyroidism
PRIMARY: caused by hyperplasia or carcinoma of parathyroid
SECONDARY: due to chronic renal failure which blocks active Vit D synthesis and therefore inhibition of PTH
Both cause hypercalcemia and kidney stones
Signs of hypoparathyroidism
Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
Paget disease
- Excessive localized regions of bone resorption and reactive sclerosis.
- Calcitonin may be of some use in its treatment
Cell types of the pancreas and their functions
(1) Beta cells [75% of islet]- Insulin
(2) Alpha cells- glucagon
(3) Delta cells- somatostatin
(4) PP cells- pancreatic polypeptide
(5) epsilon- ghrelin
Insulin + Amylin
secreted together which is why lots of insulin secretion can lead to beta cell death. Amylin proteins can build up and cause pancreatic damage.
Glucose sensing + insulin release
glucose flows into glut-2 channels and is sensed by GLUCOKINASE. This causes G6P relese of ATP and closure of K+ channel (via its SUR subunit). Depolarization causes insulin vesicles to release insulin.
Insulin Receptors
Receptor Tyrosine Kinase. Ligand binding causes autophosphorylation of beta subunit.
Insulin action mechanism
Binding to insulin receptor activates insulin receptor substrates (IRSs) which activate cascade leading to insertion of GLUT4 into membrane.
2 main pathways:
(1) PI3K (PKB) is main mediator for GLUT4 insertion
(2) MAPK mediates other growth/mitogenic actions of insulin
A cells and L cells
Both use preproglucagon
A-cells (pancreas): cleave to form and secrete glucagon
L-cells (intestines): cleave to form and secrete active GLP-1/GLP-2. These GLPs potentiate insulin release from B-cells and are stimulated by carb release in intestines.
Ghrelin
epsilon cells of pancreas
stimulates food intake and increases GH release. Inhibits insulin function
Metabolic switch
High flow of proteins from muscle mass breakdown causes ketone bodies to be used as the energy source for brain and decreases the reliance on glucose. This SAVES PROTEIN and MUSCLE MASS.
Metabolic syndrome
Usually means pre-diabetes
4 criteria
Visceral obesity; insulin resistance; dyslipidemia (too many lipids); hypertension
WAT
White Adipose Tissue
Leptin –> primary hormone
SREBP-1C
Transcription factor
promotes TG synthesis; activated by lipids and insulin
PPAR-gamma
steroid hormone
regulates TG storage and adipocyte differentiation (makes more fat cells)
TZD
uses PPAR-gamma to make more fat cells thus increasing cells available to take up glucose. Side effect = weight gain.
Name the appetite stimulators and inhibitors
STIMULATORS: neuropeptide Y; AGRP
INHIBITORS: aMSH; cocaine-amphetamine regulated transcript (CART)
Numbers for T2DM diagnosis
HbA1C (average plasma glucose [ ]) > 48mMol or 6.5%
Fasting blood glucose > 125mg/dl
Oral glucose tolerance test > 200mg/dl
Treatment of T2DM
METFORMIN: first line of treatment; increases insulin sensitivity and glucose uptake; inhibits hepatic gluconeogenesis
SULFONYLUREAS: increase insulin secretion
ALPHA-GLUCOSIDASE INHIBITOR: delays intestinal absorption of carbohydrates.
Mechanism of ketoacidosis
Body thinks it’s starving –> increased lipolysis –> FFA release (hepatic precursor for ketone acids) –> metabolism of ketone bodies –> blood acidity –> ketoacidosis
Main reason for altered mental status with uncontrolled diabetes
extremely high plasma osmolality
Critical genes expressed during islet cell development
PDX-1: important for islet neogenesis + beta cell proliferation
TCF72: downstream targets which regulate beta cell proliferation
Incretin
synthetic which looks to decrease blood glucose levels. Some positive effects on insulin function. GLP is main incretin. Released due to carbs in intestines.
EPO
Erythropoietin:
Kidney hormone which stimulates RBC increase. If hematocrit raises too quickly, there will be hypertension.
ANP/BNP
secreted from heart in response to stretch. Potent vasodilators and increase sodium excretion. Higher levels with CHF and renal failure. Lower levels with obesity. Increases with age. Women have twice as much
Endocrine disruptor
chemicals that interfere with body’s endocrine system and produce adverse effects.
Ex.’s PCB and DES
PCB
competes with thyroid hormone for binding to transport protein. Circulating thyroid hormone is degraded faster causing compensatory production increase and thus goiter.
DES
synthetic estrogen once given to pregnant women to reduce birth complications. Led to 40% increase in vaginal/cervical cancer for the daughters.
Major steroid hormones
CORT, Androgens, Estrogens, Vit D
Major Peptides/protein hormones
Insulin, PTH, pituitary and hypothalamic releasing hormones
Amine Hormone
T3/T4, Catecholamines, Indoleamines
DHEA from adrenal gland serves as a precursor for what?
Testosterone in the testes
PeVN
Periventricular Nuclei
Secretes Somatostatin (GHRH Inhibitor)
