mechanism hormone disease (lec 3)

1

Mechanisms of endocrine disease

• Endocrine disorders result from hormone deficiency, hormone excess or hormone resistance

• Almost without exception, hormone deficiency causes disease – One notable exception is calcitonin deficiency

2

Cellular Mechanisms of Hormone Action

• Target cell – recognize, bind and initiate

• Up – regulation

• Down – regulation

• Hormone effects– Direct – stimulation– Permissive – facilitates maximum

response/function

4


• Deficiency usually is due to destructive process occurring at gland in which hormone is produced—infection, infarction, physical compression by tumor growth, autoimmune attack

Type I Diabetes

5


• Deficiency can also arise from genetic defects in hormone production—gene deletion or mutation, failure to cleave precursor, specific enzymatic defect (steroid or thyroid hormones)

Congenital Adrenal Hyperplasia

6

Mechanisms of endocrine disease• Inactivating mutations of receptors can

cause hormone deficiency

Testicular Feminization Syndrome

7


• Hormone excess usually results in disease

• Hormone may be overproduced by gland that normally secretes it, or by a tissue that is not an endocrine organ.

• Endocrine gland tumors produce hormone in an unregulated manner.

Cushing’s Syndrome

8

Mechanisms of endocrine disease• Exogenous ingestion

of hormone is the cause of hormone excess—for example, glucocorticoid excess or anabolic steroid abuse

9


• Activating mutations of cell surface receptors cause aberrant stimulation of hormone production by endocrine gland.– McCune-Albright syndrome usually

caused by a mutation in a gene called GNAS1 (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide 1).

10


• Malignant transformation of non-endocrine tissue causes dedifferentiation and ectopic production of hormones

• Anti-receptor antibodies stimulate receptor instead of block it, as in the case of the common form of hyperthyrodism.

Grave’s Disease

11


• Alterations in receptor number and function result in endocrine disorders

• Most commonly, an aberrant increase in the level of a specific hormone will cause a decrease in available receptors

Type II diabetes

12

Adrenal Gland

Adrenal glands are located on the top of both kidneys.

Each gland consists of a medulla, the center of the gland, encased by a cortex.

13

Adrenal Glands• Adrenal cortex

– 80% of an adrenal gland’s total weight– Zona glomerulosa – aldosterone 15%– Zona fasciculata – glucocorticoids 78%– Zona reticularis – androgens and estrogens

(others) – 7%

• Adrenal medulla

– Innervation by SNS

14

Adrenal Glands

15

-Inner part “medulla”: -Chromaffin cells-Source of catecholamines (Epi/NEpi),-Innervated by pre-ganglionic sympathetic fibers; forms an

extension of the sympathetic nervous system (fight/flight).

-Outer part “cortex”: -Source of steroid hormones

-Glucocorticoids, mineralocorticoids and sex steroids

Anatomy/Physiology of Adrenal Gland

16

DHBR

NADP+

NADPHfrom phe, diet, or protein breakdown

Tyrosine L-Dopa

H2OO2

Tyrosine hydroxylase(rate-determining step)

BH2BH4

1

Dopadecarboxylase

CO2

Dopamine

pyridoxalphosphate

2

Dopamine hydroxylase

ascorbateH2O

Norepinephrine

O23

NMT

SAM SAH

Epinephrine

4

Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin; DHBR, dihydrobiopterin reductase; NMT, N-CH3 transferase; SAH, S-adenosyl-homocysteine; SAM, S-adenosylmethionine

Parkinson’s disease: local deficiency of dopamine synthesis; L-dopa boosts productionNMT specific to

adrenal medulla

SAM from metabolism of Met

DPN OHase in neuro-scretory granules

17

........

acetylcholine

Adrenal MedullaChromaffin Cell

Neuron

Acuteregulation

Tyrosine

L-Dopa DPN

DPN NE

granuleinduction

Chronicregulation

Stress

Hypothalamus

ACTH

Cortisolfrom adrenal cortex via intra-adrenal portal system

EpinephrinePNMT

NE

neuro-secretorygranules

E E ENE E

Regulation of the release of catecholamines and synthesis of epinephrine in the adrenal medulla chromaffin cell.

promotesexocytosis

................

EEEENE

E

E E

NE

E

Ca2+

18

Norepinephrine

Epinephrine COMT + MAOVanillylmandelic acid

Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine oxidase (MAO) and catechol‑O‑methyl-transferase (COMT)

Neuronal re-uptake and degradation of catecholamines quickly terminates hormonal or neurotransmitter activity.

Cocaine binds to dopamine receptor to block re-uptake of dopamine

Dopamine continues to stimulate receptors of the postsynaptic nerve.

Dopamine Homovanillic acidCOMT + MAO

19

Classification of Adrenergic Hormone Receptors

Receptor AgonistsSecond

MessengerG protein

alpha1 (1) E>NE IP3/Ca2+; DAG Gq

alpha2 (2) NE>E cyclic AMP Gi

beta1 (1) E=NE cyclic AMP Gs

beta2 (2) E>>NE cyclic AMP Gs

E = epinephrine; NE = norepinephrine

Synthetic agonists:isoproterenol binds to beta receptorsphenylephrine binds to alpha receptors (nose spray action)

Synthetic antagonists: propranolol binds to beta receptors phentolamine binds to alpha receptors

20

Metabolic and muscle contraction responses to catecholamine binding to various adrenergic receptors.

Process

1-receptor

(IP3, DAG)

2-receptor

( cAMP)

1-receptor

( cAMP)

2-receptor

( cAMP)

Carbohydratemetabolism

liver glycogenolysis

No effect No effect

liver/muscle glycogenolysis; liver gluconeogenesis; glycogenesis

Fatmetabolism

No effect lipolysis lipolysis No effect

Hormonesecretion

No effect insulin, renine secretion

No effect insulin, glucagon and renin secretion

Muscle contraction

Smooth muscle - blood vessels, genitourinary tract contraction

Smooth muscle - some vascular;GI tract relaxation

Myocardial - rate, force

Smooth muscle relaxation - bronchi, blood vessels, GI tract, genitourinary tract

21

1 or 2

receptor

ATP cyclic AMP

Gs

s

GTP

inactiveadenylylcyclase

GTP

ACTIVEadenylylcyclase

inactiveadenylylcyclase

2 receptor

Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity

Gi

i

GTPs

GTP

i

X

22

"FIGHT OR FLIGHT" RESPONSE

epinephrine/ norepinephrine major elements in the "fight or flight" response

acute, integrated adjustment of many complex processes in organs vital to the response (e.g., brain, muscles, cardiopulmonary system, liver)

occurs at the expense of other organs less immediately involved (e.g., skin, GI).

epinephrine: rapidly mobilizes fatty acids as the primary fuel for muscle action increases muscle glycogenolysismobilizes glucose for the brain by hepatic glycogenolysis/

gluconeogenesis• preserves glucose for CNS by insulin release leading to reduced glucose

uptake by muscle/ adipose • increases cardiac output

norepinephrine elicits responses of the CV system - blood flow and insulin secretion.

23

ADRENAL “CORTEX”-DERIVED STEROIDS

25

Adrenal Cortex

“all hormones derived from cholesterol”• Stimulated by adrenocorticotropic hormone (ACTH)• Glucocorticoid hormones

– Direct effect on carbohydrate metabolism– Anti-inflammatory and growth suppression effects– Influences awareness and sleep habits– Inhibits bone matrix-protein matrix– Cortisol – most potent naturally occurring

26

Adrenal Cortex

• Mineralocorticoid hormones – Aldosterone– ↑ Na+ uptake in epithelial cells – distal

nephrons– ↑ Na retention with loss of K+ and H+

– Regulation by the renin-angiotensin system

• Na+ and H2O depletion

• ↑ K+ excreteion

• ↓ blood volume

27

Adrenal “Cortex”-derived Steroids

Class Major Effects

Glucocorticoids Cortisol Glucose metabolism control

Mineralocorticoids Aldosterone Na/K/H20 control

Sex steroids DHEA Androgen precursorsAndrostendione

28

SECRETION OF INDIVIDUAL STEROID HORMONES IS

RESTRICTED TO SPECIFIC REGIONS OF THE ADRENAL

CORTEX

MEDULLA

RETICULARISCORTISOL

ANDROGENS

CAPSULE

EPINEPHRINE

NOREPINEPHRINE

ALDOSTERONEAD

REN

AL

CO

RTEX

MEDULLARETICULARIS

MEDULLA

GLOMERULOSA

FASCICULATA

29

SYNTHESIS OF ADRENAL CORTEX HORMONES

30

Hypothalamus

Anterior pituitary

Adrenal cortex

Corticotropin-releasing factor (CRF)

Adrenocorticotropic hormone (ACTH)

Glucocorticoids(especially cortisol)

HypoxiaHypoglycemiaHyperthermia

ExerciseCortisol insufficiency

Stress

Diurnal rhythms

( - )

SomatostatinHypothalamic

lesions

( - )

(+)

(+)(+)

31

minus side chain

ALL STEROIDOGENIC TISSUES

CHOLESTEROL (C27)

+ 3-keto

+ 11-OH

PROGESTERONE

+3-keto

+ 21-OH

+ 3-keto

+ 11-OH

+ 21-OH

+ 17-OH

CORTISOL (C21)

CORTICOSTERONE

ALDOSTERONE (C21)

+ 20-keto

+ 17-OH

PREGNENOLONE (C21)

ANDROSTENEDIONE (C19)

+ 18-ALDEHYDE

TESTOSTERONE

ESTRADIOL (C19)

GONADS

ADRENAL CORTEX

ESTRONE

STEROID SYNTHESIS

DEHYDROEPIANDROSTERONE” ’’DHEA”

17-OH PROGESTERONE

DEHYDROEPIANDROSTERONE SULFATE (C19 :“DHEA-S”)

+ 3-keto

aromatase

17-OH PREGNENOLONE

DIHYDROTESTOSTERONE (C19)

sulfotransferasedesmolase

desmolase

aromatase

Adrenals

32

ENDOPLASMIC RETICULUM

OXIDATION OF STEROID NUCLEUS BY SPECIFIC P-450 HYDROXYLASES

5 - PREGNENOLONE (C21)

ALDOSTERONE

ANDROGEN PRECURSORS

11-DEOXYCORTISOL

SYNTHESIS AND “SECRETION” OF STEROID HORMONES BY ADRENAL CORTEX

GONADS

Cholesterol in

IntracellularLipid droplets

2

1

3

KIDNEY

DIFFUSION OF STEROIDS OUT OF CELL

CORTISOL

CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM INTRACELLULAR CHOLESTEROL ESTERS “STORED”

IN LIPID DROPLETS

UPTAKE OF CHOLESTEROLESTER FROM LDL AND HDL

IN PLASMA

P450

scc

StAR facilitates transfer ofcholesterol molecules between

inner and outer membranes

4

17-OH PROGESTERONE

REMOVAL OFSIDE CHAIN

StA

R

P450c11

11-HYDROXYLASE

33

The metabolic effects of glucocorticoids

They increase glucose production by:1. Increasing the supply of amino acids to the liver2. Activating the expression of genes of gluconeogenic enzyme

Promote lipolysis in peripheral tissues by inducing enzyme synthesis

(Increase mobilization of peripheral fat)

When at very high levels can cause lipogenesis in face and trunk

When at a very high levels has catabolic effect on proteins in peripheral tissues and anabolic effect in the liver

34

The metabolic effects of glucocorticoids

When at very high levels can cause lipogenesis in face and trunk

35

Cortisol (hydrocortisone) and synthetic glucocorticoids (prednisone): Potent anti-inflammatory and immunosuppressive agent [topical, oral, aerosolized, injection]

Therapeutic Effects of Glucocorticoids

-used to relieve symptoms of inflammation [swelling, heat, redness, and pain];

-used in cases of insufficient synthesis (hormone replacement);

-used to treat certain forms of arthritis; skin, blood, kidney, eye, thyroid, and intestinal disorders (e.g., colitis); severe allergies; and respiratory conditions such as asthma.

-used in the treatment of certain types of cancer.

36

A glucocorticoid interaction with its receptor results in increasing the transcriptionof the protein IB, which binds and inhibits the activity of NF-B, a a transcriptionalactivator that stimulates transcription of genes for inflammatory cytokines. NF-Bis normally sequestered in an inactive state through association with IB proteins.(TNF is a proinflammatory cytokine.)

Glucocorticoid induction of IB synthesis through GCbinding to its intracellularreceptor and stimulating trans-cription of the gene.

IB binds toand inhibits thenuclear translo-cation of NF-B.

NF-B stimulates theultimate production ofinflammatory cytokinesTumor necrosis factor (TNF)

binding to its receptor leads tothe ultimate degradation of IB

How glucocorticoids suppress immune and inflammatory reactions mediated by cytokines

37

Adrenal Gland Steroids

Cortisol (the naturally-occurring glucocorticoid) levels are regulated by a hypothalamus-pituitary-adrenal hormone axis.

Corticotropin releasing hormone (CRH) controls adrenocortioctropic hormone (ACTH) release from the pituitary.

ACTH is a trophic hormone that stimulates:

-synthesis and secretion of cortisol and

-growth of the adrenal gland.

When cortisol levels increase, CRH and ACTH secretion/release are reduced.

38

Mineralocorticoids

Mineralocorticoids (e.g. aldosterone)-enhance renal tubular retention of Na+, HCO3- and water

and increase excretion of K+: this increases serum Na and decreases serum K

-increased blood volume and pressure

Removal of the adrenal glands leads to death within just a few days due to:

-the concentration of potassium in extracelluar fluid becomes dramatically elevated; -urinary excretion of sodium is high and concentrations of sodium in extracellular fluid decreases significantly; -volume of extracellular fluid and blood plummet; -the heart begins to function poorly, cardiac output declines and shock ensues

39

Control over aldosterone secretion is multifactorial:

-The two most significant regulators of aldosterone secretion are:

•Concentrations of K+ in extracellular fluid: Small increases in blood levels of potassium strongly stimulate aldosterone secretion.

•Angiotensin II: Activation of the renin-angiotensin system as a result of decreased renal blood flow (usually due to decreased vascular volume) results in release of angiotensin II, which stimulates aldosterone secretion

Control of Aldosterone Secretion

40

Adrenal Insufficiency (Addison’s disease, 1:100,000)

Primary Adrenal Insufficiency:

-most common cause is autoimmune-mediated destruction of the adrenal glands (>80%)

-secondary to tuberculosis, chronic fungal infections, infection by cytomegalovirus (CMV), metastasis to the glands by cancer cells (~20%)

Secondary Adrenal Insufficiency:

-Addison’s Disease caused by inadequate secretion of ACTH by the pituitary gland;

-may arise due to the prolonged or improper use of glucocorticoid hormones( temporary);

Disorders of the Adrenal Gland

41

Cushing’s Syndrome

-Cushing's Syndrome is EITHER a disease caused by an excess of cortisol production, or a disorder resulting from excessive use of glucocorticoids

Disease-related excess production of cortisol (2 types):1) Excess ACTH Production: Ex. A pituitary tumor producing too much ACTH

stimulates adrenal growth and increases cortisol (>70%); Also "ectopic" ACTH production (30%)

2) Adrenal cortex tumours: Tumours can be benign (an adenoma), or malignant (a carcinoma). Usually found on only one side.

Disorders of the Adrenal Gland

42

Hormones and stress • Stress = any condition that threatens homeostasis• GAS (General Adaptation Syndrome) is our bodies

response to stress-causing factors• Three phases to GAS

– Alarm phase (immediate, fight or flight, directed by the sympathetic nervous system and dominated by the catecholamines)

– Resistance phase (dominated by glucocorticoids)

– Exhaustion phase (breakdown of homeostatic regulation and failure of one or more organ systems)

43

The General Adaptation Syndrome

44


Figure 18.21

45


46

Retinoid Hormones• Isoprenoid hydrophobic

hormones.• The pro-hormone, retinol, is

made in the liver.• Retinol is converted to the

hormone, retinoic acid, by many tissues.

• Retinoic acid regulates cell growth and development in most cells, but the principal targets are the cornea, skin and epithelia.

• Excess Vitamin A can cause birth defects and liver damage.

• Severe acne is treated with retinoid creams.

47

THYROID HORMONES

48

The Thyroid Gland

Figure 18.11b, c

Thyroglobulin is a protein rich in Tyr (100Tyr/1molecule)

49

Synthesis of T3 and T4

The thyroid gland: Synthesizes and secretes triiodothyronine-T3 and thyroxine-T4

-the only body tissue that can accumulate iodide

Steps of thyroid hormone synthesis-accumulation of iodide via a specific iodide pump.-iodinatition of tyrosine produces monoiodotyrosine (MIT) and

diiodotyrosine (DIT)- coupling reaction: Synthesis of MIT/DIT: -MIT +DIT produces T3 (3 iodine) -DIT+DIT, T4 (4 iodine). -MIT/DIT are complexed with thyroglobulin.-Thyroglobin proteolysis liberates T3 and T4- Released hormones are secreted: 5(T4) to 1(T3).

50

TYROSINE IODINATION

CH2CHCOOH-

NH2

HO TyrTYROSINE

CH2CHCOOH

HO

CH2CHCOOH-

NH2

HOMONOIODOTYROSINE (MIT)

DIIODOTYROSINE (DIT)

I

I

NH2

TYROSINE IODINATION

I

I

SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION

Approximately 10% of the tyrosine residues on the 550 amino acid residue Thyroglobulin molecule may become iodinated by the enzyme - thyroid peroxidase acting on the colloid at the luminal surface of the thyroid follicle. These reactions only occur in the thyroid at specific residues in “Hormonogenic” sites located at the extreme ends of the Thyroglobulin molecule.

Tyr

Tyr

THYROGLOBULIN

THYROGLOBULIN

THYROGLOBULIN-

51

Thyroglobulin

CH2CHCOOH

Thyroglobulin

I

I

Tyr

3,5,3’5’-tetraiodothyronine

SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES

CH2CHCOOH

NH2

+HO

II

I

Tyr

NH2

T4

Thyroglobulin

I

I

Tyr CH2CHCOOH

NH2

CH2CHCOOH

I

Tyr

NH2

Thyroglobulin

Tyr

II

I

Tyr O

+

IT3

3,5,3’-Triiodothyronine

Coupling of iodotyrosine moities results in the loss of the peptide linkage to thyroglobulin allowing thyroid hormones to diffuse across the cell membrane

II

Tyr

II

I

Tyr O

I

33’

5 5’

HO

HO

HO

HO

HO

53

3,5,3’5’-tetraiodothyronine

CH2CHCOOH

NH2

CH2CHCOOH

3,3’,5’-Triiodothyronine (reverse T3)

NH2

Tyr

II I

Tyr O

rT3

I

3,5,3’-Triiodothyronine (T3)

II

Tyr

II

I

Tyr O

T4I

T3

Tyr

II I

Tyr O

I

5’- deiodination5-deiodination

CH2CHCOOH

“ACTIVATION” PATHWAYIn peripheral tissues

“DEACTIVATION” PATHWAY

NH2

STEP 3

DEIODINATION

SELENODEIODINASES

54

TG

SECRETION OF THYROID HORMONE

IODINATION OF THYROGLOBULIN BY THYROID PEROXIDASE

“DIFFUSION” OF THYROXINE THROUGH CELL MEMBRANE

DEGRADATION OF THYROGLOBULIN

FUSION OF PHAGOSOME WITH LYSOSOMES

ENDOCYTOSIS OF ‘COLLOID’ IN FOLLICLE BY

PSEUDOPOD

TG

TG

TG

T4

T4 T3>> >

I

IODIDE UPTAKEBY Na/I

SYMPORTER

IODIDE IN ECF~20nM

DEGRADATIONAND

RECYCLINGOF MIT/DIT

BY DEIODINASES

Other monovalent anions compete with iodide for uptake; sometimes with useful medical and experimental applications e.g.

TCO 4;Cl0 4; SCN;

FREE THYROXINE RELEASED FROM PROTEIN INTO CYTOPLASM

TG

2

1

3

4

5

6

7

8

Additional metabolism??

55

THYROID HORMONES

HORMONERELATIVE POTENCY

PRODUCTION t½

(µg/day)

4-8 (24)*

BOUND TO PLASMA

PROTEINS

(%)

-

99.95

(days)

80- 90 8

0.04 99.8 0.1

+ + + +

rT3

VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION

2-3 (27) *

1-3

6-7+T4

T3

*

(µg/dL)

PLASMACONCENTRATION

0.3 99.7

56

Regulated T3/T4 Release

T3/T4 synthesis/release is tightly regulated:

-reduced T3/T4 stimulates TRH release from the hypothalamus (HPT) which then causes TSH release from the pituitary (PIT).

TSH stimulates:

1) T3/T4 synthesis and secretion

2) thyroid gland growth.

When T3/T4 levels increase, negative feedback shuts off TRH and TSH secretion.

57

Physiological Actions of T3/T4

Play a Central Role in Regulating:

-growth/development of most cells,-basal metabolic rate and temperature (stimulate cellular respiration)-cardiac output by increasing rate/force of contraction,-metabolism of cholesterol to bile acids,-LDL receptor expression in hepatocytes,-TSH secretion

THYROID HORMONES ARE ESSENTIAL TO LIFE!

58

Symptoms include: fatigue/weakness, weight gain/difficulty losing weight, coarse/dry hair, dry/rough pale skin, cold intolerance, muscle cramps/muscle aches, constipation, depression, irritability, memory loss, abnormal menstrual cycles, decreased libido

-Myxedema coma: A medical emergency characterized by hypothermia, hypotension, hypoventilation and bradycardia represents the extreme expression of severe hypothyroidism

Hypothyroidism (Myxedema)Reduced circulating T3/T4 levels

59

Problems with the Thyroid Gland

Hyperthyroidism:• high metabolic rate, hyperactivity, sensitivity to heat, protruding eyes• Grave’s disease: when hyperthyroidism is due to an autoimmune problem

(TSH is mimicked by autoantibodies)

Hypothyroidism:• in the adult: myxedema- low metabolic rate, sensitivity to cold,

sluggishness, weight gain/difficulty losing weight, coarse/dry hair, dry/rough pale skin, constipation, depression, irritability, memory loss, abnormal menstrual cycles, decreased libido

• in an infant: cretinism-- stunted growth, mental retardation, abnormal bone formation

• Hashimoto’s disease: when hypothyroidism is due to an autoimmune problem (autoantibodies attack and destroy follicular cells)

• goiter no T3 and T4 can be made because not enough iodides were ingested.

60

Primary Hypothyroidism (Myxedema)

-When synthesis of T3/T4 is low, no feedbackinhibition of TSH occurs and TSH levels rise.-TSH stimulation of the thyroid gland is increased and lead to:

-the lack of T3/T4 synthesisin primary hypothyroidism leads toTSH-mediated increases in size (goiter).

61

Secondary Hypothyroidism

When the pituitary can't make TSH there is no signal to the thyroid gland to make T3/T4. Thus secondary hypothyroidism is (i.e. pituitary- mediated) associated with decreased T3/T4 AND TSH and thyroid atrophy.

62

Primary hyperthyroidism: Thyroid secretes T3/T4 in a TSH unregulated fashion

Symptoms: -heart palpitations, heat intolerance, nervousness, insomnia, breathlessness,increased bowel movements, light/absentmenstrual periods and fatigue

Primary Hyperthyroidism

63

Loss of T3/T4-mediated negative effects on TSH release by pituitary

-the thyroid is chronically stimulated to synthesize and secrete T3/T4 and to grow. Thus ,goiter is also a symptom of secondary hyperthyroidism

Secondary Hyperthyroidism

64

Relief of direct symptoms: Drugs that inhibit thyroid hormone production/release (methimazole, propylthiouracil (PTU):

-Inhibit hrmone synthesis (iodine organification) -Inhibit MIT coupling

Limitations: The symptoms associated with hyperthyroidism return when the drugs are discontinued.

Hyperthyroidism-Treatments

65

Radioactive Iodine:[135I]-most widely recommended permanent treatment ofhyperthyroidism

-treatment takes advantage of the fact that only thyroid cellscan incorporate iodine

-[135I] emits gamma (γ) radiation: Directly kills thyroid cells

-There is no evidence that [135I] treatment for hyperthyroidism causes cancer of the thyroid gland or of any other tissue

Hyperthyroidism-Treatments

66

BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL SUBSTANCE?

The observation that calcitonin (CT) at supraphysiological doses is hypocalcemic, led to the mistaken conclusion that it was important for calcium homeostasis and this idea has persisted to this day. Despite these findings there is no apparent pathology due to CT excess or deficiency and there is no evidence that circulating CT is of substantial benefit to any mammal.

Mammalian CT at physiological doses is not essential and very likely the CT gene has survived because of the gene’s alternate mRNA pathway to produce calcitonin-gene-related peptide CGRP found in neural tissues.

HIRSCH,PF and BARUCH H, ENDOCRINE 2003, 201-208

CALCITONIN IS SECRETED FROM THE THYROID PARAFOLLICULAR CELLS

67

THE PARATHYROID HORMONE

68

Parathyroid Gland• This gland only secretes

one hormone: Parathyroid Hormone (or PTH)

• PTH function (we began learning this when we studied bone):– increases blood

calcium (Ca2+) levels and decreases blood phosphate (PO4

2-) levels

69

PTH function (continued)

• How does PTH work?– PTH causes Ca2+ & PO4

2- to be released from bone into blood (by increasing osteoclast activity)

– PTH decreases the excretion of PO42- ions

through urine– PTH increases calcitriol production, so that

more Ca2+ is absorbed during digestion• PTH is regulated by blood calcium levels-- not

by other glands!

70Figure 18.15

The Regulation of Calcium Ion Concentrations

71

THE PANCREATIC HORMONES

72

The pancreatic islets

• Clusters of endocrine cells within the pancreas called Islets of Langerhans or pancreatic islets– Alpha cells secrete glucagons– Beta cells secrete insulin– Delta cells secrete GH-IH– F cells secrete pancreatic polypeptide

73

The Endocrine Pancreas

Figure 18.18a, b

74

BLOOD FLOWS RADIALLY FROM CENTER OF ISLET TO THE

PERIPHERY FACILITATING PARACRINE INHIBITION OF

GLUCAGON SECRETION BY INSULIN

VENOUS BLOOD

ISLETS OF LANGERHANS

MANTLE FORMED BY CELLS

SECRETING GLUCAGON (20-25%)

CORE FORMED BY BETA CELLS

SECRETING INSULIN

(60-70 % OF TOTAL)

1 MILLION ISLETS EACH

CONTAINING 2500 CELLS

ARTERIAL BLOOD

VENOUS BLOOD

CELL CELL

SECRETORY

GRANULES

Ca

na

licu

lus

76

Endocrine Pancreas

• Insulin– Synthesized from proinsulin– Secretion is promoted by ↑ blood glucose– Facilitates the rate of glucose uptake into

the cells– Anabolic hormone

• Synthesis of proteins, lipids and nucleic acids

77

Endocrine Pancreas• Glucagon

– Secretion is promoted by decreased blood glucose levels

– Stimulates glycogenolysis, gluconeogenesis and lipolysis

• Somatostatin (delta cells)– Regulation alpha and beta cell secretions

78

PHYSIOLOGICAL ROLE OF INSULIN

MAINTENANCE OF NORMAL PLASMA GLUCOSE LEVELS IN SPITE OF

LARGE CHANGES DUE TO FOOD INTAKE

PRESERVATION OF ENERGY STORES

STIMULATION OF GLUCOSE TRANSPORT

STIMULATION OF GLUCOSE UTILIZATION

RAPID UPTAKE OF DIETARY GLUCOSE

UTILIZATION OF DIETARY GLUCOSE

STIMULATION OF GLUCOSE OXIDATION

STIMULATION OF LIPID SYNTHESIS

STIMULATION OF GLYCOGEN SYNTHESIS

INHIBITION OF GLYCOGEN DEGRADATION

INHIBITION OF GLUCONEOGENESIS

INHIBITION OF LIPOLYSIS

INHIBITION OF PROTEOLYSIS

AF

TE

R A

ME

AL

DU

RIN

G A

FA

ST

79

Endocrine Pancreas

80Figure 18.19

Figure 18.19 The Regulation of Blood Glucose Concentrations

81

THE PINEAL GLAND

82

Pineal Gland

Secretes only one hormone: melatonin

- involved in your circadian rhythm (your recognition of day and night times):

– melatonin secretion decreases in the day

– melatonin secretion increases at night

Melatonin is also involved in longer rhythms, like monthly and seasonal

- inhibits reproductive function

- protects against damage by free radicals

- has anti-ageing, anti-cancer effects

83

The Endocrine Functions of Other Organs

84

The intestines

• Produce hormones important to the coordination of digestive activities

85

The kidneys

• Produce calcitriol and erythropoietin (EPO) and the enzyme rennin– Calcitriol = stimulates calcium and phosphate ion

absorption along the digestive tract– EPO stimulates red blood cell production by bone

marrow– Renin converts angiotensinogen to angiotensin I

86

Angiotensin I converted to angiotensin II in the lungs

• Stimulates adrenal production of aldosterone• Stimulates pituitary gland release of ADH• Promotes thirst• Elevates blood pressure

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Endocrine Functions of the Kidneys

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Endocrine Functions of the Kidneys

LUNGS

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The heart

• Specialized muscle cells produce natriuretic peptides when blood pressure becomes excessive– Generally oppose actions of angiotensin II

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The thymus

• Produces thymosins– help develop and maintain normal immune

defenses– are involved in white blood cell production

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Adipose tissues secrete

• Leptin, a feedback control for appetite

• Resistin, which reduces insulin sensitivity

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The gonads• Interstitial cells of the testes

produce testosterone– Most important sex hormone

in males• In females, oocytes develop in

follicles– Follicle cells produce

estrogens• After ovulation, the follicle cells

form a corpus luteum that releases a mixture of estrogens and progesterone

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I fought the law, but the law won…..

mechanism hormone disease (lec 3)

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