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Flashcards in Endocrine Deck (116):
1

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

2

Rate limiting step of catecholamine formation

Tyrosine Hydroxylase conversion of Tyrosine to XDOPA

3

Function of Dopamine

Tonic Inhibitor of prolactin release from anterior pituitary

4

Defining component of Catecholamines and the main type(s).

Derived from single tyrosine

-Dopamine, Epi, NE

5

Defining component of Indoleamines and the main type(s)

Derived from single tryptophan

-Serotonin is the main one (and melatonin comes from serotonin)

6

Rate limiting step of indoleamine formation

Tryptophan hydroxylase conversion of Tryptophan to an intermediate

7

Function of serotonin and where it is made.

95% made in gut. Acts as a vasoconstrictor and stimulates smooth muscle cell contraction in intestine.

8

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

9

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.

10

PVN

Paraventricular Nucleus

CRH, TRH (anterior pit); AVP, OXY (posterior pit)

Thirst, BP, mood/emotion/stress

11

POA

Preoptic Nucleus

GnRH

Reproduction

12

ARC

Arcuate Nucleus

Growth Hormone Releasing Hormone (GHRH)

Feeding behavior, satiety

13

SCN

Suprachiasmatic Nucleus

Sleep, Circadian Rhythms

14

ME

Medial Eminence

Functional converging point for neurons of hypothalamus, where they all release their hormones

15

GnRH pulsatility every 30 -60 mins favors...

every 2-3hrs...?

30-60mins: LH

2-3hrs: FSH

16

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).

17

Neurohypophysial Tract

Posterior Pituitary

Comprises neurons whose axons terminate in the posterior pituitary.

18

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)

19

What composes 90% of the Anterior Pituitary?

Pars distalis

20

Herring Bodies

Dilations of unmyelinated axons near the terminals which serve as the site of hormone release for the POSTERIOR PITUITARY.

21

Prolactin vs Oxytocin

Prolactin: Milk production, mammory gland development and breast differentiation
Oxytocin: Milk ejection

22

Carrier for AVP? For Oxytocin?

AVP- neurophysin II

Oxy- neurophysin I

23

ADH is secreted from what cells?

Magnocellular (posterior pit): fluid balance

Paracellular (median eminence): stress/anxiety

Both are cells of the PVN

24

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

25

Specific cell for release of oxytocin

Magnocellular neurons whose cells are located in PVN

26

Somatostatin

Inhibits pulsatile frequency of GHRH and thus blocks GH and TSH release from pituitary.

Also suppresses insulin release

27

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

28

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.

29

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

30

Adult GH deficiency

(1) Caused by tumor/surgery or treatment
(2) increased fat deposition
(3) reduced bone density
(4) High LDL/TGs

31

Prolactin stimulation

Mainly by TRH (Thyrotropin-releasing hormone) and also oxytocin

Produced by hypothalamus to stimulate release of TSH and prolactin from anterior pituitary.

32

Prolactin inhibits release of what hormone?

GnRH --> which is why breast feeding moms don't easily get pregnant.

33

CRH binds with highest affinity to what receptor?

CRH R1 in anterior pituitary to activate G-protein induced PKA pathway

34

What two hormones act synergistically to increase amplitude of ACTH release from the anterior pituitary?

-AVP
-CRH

35

Preprohormone of ACTH

POMC gene

36

Main ACTH action in adrenal gland

Stimulate biosynthesis of glucocorticoids

37

ACTH receptor

MC2R --> high affinity
MC1R --> low affinity (found in skin, causes hyper-pigmentation with high levels of ACTH)

38

Adrenal gland secretions by layer

Z. GLOMERULOSA: mineralocorticoids
Z. FASCICULATA: glucorticoids (cortisol)
Z. RETICULARIS: weak androgens (DHEA)

MEDULLA: catecholamines

39

Cortisol transport

CBG (corticosteroid binding globulin). Used to transport 90% of circulating cortisol in the blood.

Decreased by estrogen or shock/severe infection

40

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.

41

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

42

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.

43

How does Cortisol increase fat breakdown and redistribution

MAG lipase and Hormone sensitive lipase (HSL)

44

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

45

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

46

Addison's disease

Autoimmune destruction of adrenals

47

Mineralocorticoids

Hormones that promote sodium retention by the kidney. Water retention = secondary result.

ALDOSTERONE --> main mineralocorticoid

48

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

49

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)

50

Licorice and sodium/water retention

Increased licorice = inhibition of 11B-HSD2 = increased cortisol levels = cortisol activation of MR = increased sodium and water retention

51

DHEA

Precursor for testosterone and estrogens

52

Universal first step of steroid hormone biosynthesis

Conversion of cholesterol to pregnenolone via CYP11A1 side-chain removal

53

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

54

Major cell type of the adrenal medulla and what causes its secretions

Chromaffin cells.

Stimulated to secrete catecholamines via spinal cord

55

Function of cortisol on NE

Cortisol stimulates conversion of NE to Epi, in the adrenal medulla

56

What works to degrade catecholamines?

COMT and MAO

57

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.

58

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

59

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

60

Two precursors needed for thyroid hormone formation

Thyroglobulin (TG) and iodide

61

Minimum iodide intake for thyroid deficiency

20 ug/day (400 ug/day is average in U.S.)

62

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.

63

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)

64

Inhibition of TSH release

Negative feedback of T3. Also Dopamine and somatostatin function tonically inhibit TSH function.

65

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

66

Carbimazole (methimazole)

Inhibits thyroid peroxidase. Used as treatment for hyperthyroidism because iodide can no longer become iodine

67

NIS

Sodium iodide symporter which brings iodide into thyroid

68

Cold vs Hot spot

Seen during thyroid autoradiographs.

Cold = white spot surrounded by black = cancer
Hot= black spot surrounded by white = hyperthyroidism

69

Organification defect

Iodide cannot be incorporated into tyrosine

70

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

71

T3 and the CNS

T3 is critical for normal brain development.

-neuronal cell migration/differentiation
-myelination
-synaptic transmission

72

Grave's disease

Hyperthyroid

Autoimmune antibodies stimulate TSH via Long-acting thyroid stimulator (LATS)

Elevated T3/T4

73

Hashimoto's Thyroiditis

Hypothyroid

Autoimmune destruction of thyroid follicles.

Antibodies against TPO (thyroid peroxidase) , TG (thyroglobulin)

74

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

75

What cells secrete PTH

The chief cells of the parathyroid gland

76

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.

77

OPG

Osteoprotegrin

Antagonist of RANK-L (and therefore is anti-bone breakdown). Works as RANK-L receptor decoy.

Stimulated by estrogens; inhibited by glucocorticoids

78

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

79

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.

80

Calciferol

General term for Vit D

81

Calcidiol

Aka Calcifidiol or 25-hydroxyvitamin D. Immediate precursor to active Vit D.

Formed in liver.

82

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.

83

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)

84

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

85

Signs of hypoparathyroidism

Chvostek sign: twitching of facial muscles in response to tapping of facial nerve

86

Paget disease

-Excessive localized regions of bone resorption and reactive sclerosis.
-Calcitonin may be of some use in its treatment

87

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

88

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.

89

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.

90

Insulin Receptors

Receptor Tyrosine Kinase. Ligand binding causes autophosphorylation of beta subunit.

91

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

92

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.

93

Ghrelin

epsilon cells of pancreas

stimulates food intake and increases GH release. Inhibits insulin function

94

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.

95

Metabolic syndrome

Usually means pre-diabetes

4 criteria

Visceral obesity; insulin resistance; dyslipidemia (too many lipids); hypertension

96

WAT

White Adipose Tissue

Leptin --> primary hormone

97

SREBP-1C

Transcription factor

promotes TG synthesis; activated by lipids and insulin

98

PPAR-gamma

steroid hormone

regulates TG storage and adipocyte differentiation (makes more fat cells)

99

TZD

uses PPAR-gamma to make more fat cells thus increasing cells available to take up glucose. Side effect = weight gain.

100

Name the appetite stimulators and inhibitors

STIMULATORS: neuropeptide Y; AGRP

INHIBITORS: aMSH; cocaine-amphetamine regulated transcript (CART)

101

Numbers for T2DM diagnosis

HbA1C (average plasma glucose [ ]) > 48mMol or 6.5%

Fasting blood glucose > 125mg/dl

Oral glucose tolerance test > 200mg/dl

102

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.

103

Mechanism of ketoacidosis

Body thinks it's starving --> increased lipolysis --> FFA release (hepatic precursor for ketone acids) --> metabolism of ketone bodies --> blood acidity --> ketoacidosis

104

Main reason for altered mental status with uncontrolled diabetes

extremely high plasma osmolality

105

Critical genes expressed during islet cell development

PDX-1: important for islet neogenesis + beta cell proliferation

TCF72: downstream targets which regulate beta cell proliferation

106

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.

107

EPO

Erythropoietin:

Kidney hormone which stimulates RBC increase. If hematocrit raises too quickly, there will be hypertension.

108

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

109

Endocrine disruptor

chemicals that interfere with body's endocrine system and produce adverse effects.

Ex.'s PCB and DES

110

PCB

competes with thyroid hormone for binding to transport protein. Circulating thyroid hormone is degraded faster causing compensatory production increase and thus goiter.

111

DES

synthetic estrogen once given to pregnant women to reduce birth complications. Led to 40% increase in vaginal/cervical cancer for the daughters.

112

Major steroid hormones

CORT, Androgens, Estrogens, Vit D

113

Major Peptides/protein hormones

Insulin, PTH, pituitary and hypothalamic releasing hormones

114

Amine Hormone

T3/T4, Catecholamines, Indoleamines

115

DHEA from adrenal gland serves as a precursor for what?

Testosterone in the testes

116

PeVN

Periventricular Nuclei

Secretes Somatostatin (GHRH Inhibitor)