Recommended Books.• Guyton & Hall• W.F Ganong

• Basic Medical Biochemistry, by Dawn.B.Marks & Allan D Marks., Ch No 43 Section No III., Pg No 667.

• Text Book of Medical Biochemistry, by MN Chatterjea & Rana Shindle., Fourth Edition, Chapter No 27, Section No III, Page No 494.

MOLECULAR ENDOCRINOLOGY• Endocrinology is the Branch of BioMedical sciences which deals with the Synthesis/Secretion/

Biological Effects of Hormones on biological system.

• Branch of Physiology which deals with the study of endocrine glands, hormones, their receptors, the intracellular signaling pathways and the diseases associated with them.

• What are hormones?

• Where do they come from?

• Major endocrine glands?

• Physiological processes controlled by hormones?

• The Glands/specialized tissues which are responsible for synthesis and secretion of Hormones called “ENDOCRINE GLANDS”

• HORMONE, is a chemical substance which is produced in one part of body, enters in the circulation, carried to distant target organs/tissues to modify their structures and functions.

Figure 18.1

The Endocrine System

Characteristics of HORMONE •HORMONE, a catalyst, resemble with

enzyme.•HORMONE, required only in small

amount.•HORMONE, not used up during the

reaction.•HORMONE, produced by an organ act to

other•HORMONE, secreted in circulation before

act.•HORMONE, are not protein all the time.•HORMONE, are either

proteins/G.P/Peptides amino acids/Steroids.

Figure 18.2

Hormone Structures and Synthesis, A Structural Classification of Hormones

HORMONEPROTEIN/PEPTIDE

•These are either large protein molecules or medium/small sized peptides.

•Insulin & Glucagon•Parathrombin & Calcitonine•Pituitary Hormones.

HORMONEAMINO ACID DERIVATIVES•These are derived from amino Acids e.g.

Tyrosine derived Hormones.

•Epnipherine & Nor-Epinephrine.•Thyroid Hormones. (T3 & T4)•Tri-iodo-thyronine•Tetra-iodo-Thyronine

HORMONESTEROIDS

•These are Steroid in nature such as;

• Adrenocorticoid Hormones,•Androgens.•Estrogens.•Progesterone.

CLASSIFICATION OF HORMONES(Based on their action)

• Hormones regulating Hypothalamus/Pituitary Glands. e.g. CRH (Corticotrophin Releasing Hormone) TRH (Thyrotropin Releasing Hormone)

GnRH (Gonadotropin Releasing Hormone)LH (Luteinizing Hormone) FSH (Follicle Stimulating Hormone)

• Hormones regulating Fuel Metabolism.e.g. Insulin/Glucagon/Somatostatin/Epiephrine/Nor-Epiephrine/ Glucocorticoides/T3-T4.

• Hormones regulating Na+ & Ca++ Levels e.g. Anti-Diuretic Hormone/Aldosterone/ANP/Angiotensin II/III.

• Hormones regulating Growth/Differentiation & Reproduction e.g. Growth Hormone/Insulin like growth factor/Estrogen/Progesterone/Testosterone.

The Cell Membrane Phospholipid Second Messenger System &The Intracellular Calcium-Calmodulin Second Messenger System

Chemical Mediator{Hormone/Drug/NT’s}

BIOLOGICAL RESPONSE(S)

Tertiary Messengers

PIP2

Endoplasmic Reticulum.

Angiotension –II/Catecholamine, GH, Oxytocin, GnRH

Text Book of Medical

Physiology11th ed,

Guyton & HallCh 74,

Pg No 915

IP3= Inositol TriphosphateDAG = DiAcyl Glycerol

AA = Archidonic Acid.

Recognition & Hormone

Release Signal Generation

Biological Effects.

Mechanism of action of water-soluble Hormones The Anterior Pituitary Hormones

Human Growth hormone/TSH/ACTH/FSH/LH Prolactin.1st Mes

2nt Mes

Response

Text Book of Medical Physiology11th, Guyton & HallCh 74, Pg No 913

cAMP = Cytoplasmic Adenosine Mono-phosphate.

Mechanism of Action for lipid-soluble or steroid Endocrine hormones Lipid-Soluble Hormones Aldosterone Calcitriol Testosterone

Estrogen Progesterone T3 & T4

Mechanism of Action of Steroid Hormone Vs T3 OR T4

Interacting with Surface Receptor.•RECEPTOR

Receptor is macro-molecular structure present either on cell membrane/nuclear membrane, responsible to interact with chemical messengers and or to exhibit response.

Chemical messenger are of two types; Endogenous Chemical Messenger

1) Neurotransmitter (s)2) Hormone (s)

Exogenous Chemical MessengerDrugs (Chemical Agents/Biological

Agents)

Interacting with Surface Receptor.Types of Receptor (s)

Interacting with Surface Receptor.(Conti)

•As per Heller Hypothesis there are certain molecules which can’t cross the target’s cell membrane.

• The hormones thus bind with their surface receptors present on the plasma membrane.

• They cause rapid secondary metabolic changes in the tissues.

• PROTEIN HORMONES (Insulin/Glucagon) Epinepherine/Nor-Epinephrine proceed through surface linked Recptor.

Interacting with Nuclear Receptor.• The Steroid Hormones act mostly by Nuclear action.• They change the “Transcription rate” of specific gene in

the nuclear DNA.

• Mechanism of Steroid Hormones (Testosterone/Estrogen)

• The steroid Hormone cross cell membrane and attach with Cytosolic Protein “Heat Shock Protein 90” . (THE IN-PUT)

• This “SH-HSP/90-complex” thus cross nuclear membrane.• This “SH” is separated out from HSP/90 and attach over

the “Hormone Responsive Element (HRE)” of the DNA.• The induced/steroid Hormone controlled HRE thus,

change the Transcription of specific gene in DNA which ultimately respond as synthesis of new protein/enzyme etc.

(THE OUT-PUT)

Stimulation of Enzyme synthesis at Ribosomal Level.• The activity of the ribosome at the level of

translation of genetic information is carried by the m-RNA for the synthesis of certain proteins/enzymes.

• The Growth Hormone act directly on the Ribosomal Level and augmented the final outcome of protein (for structural development) and enzymes (for accelerated metabolic fate).

Direct Activation at Enzyme Level• Although the direct effect of a hormone on a

pure enzyme is difficult to demonstrate.

• But the treatment of the intact animal or isolated tissues with some hormones results in a change of enzyme activity, not related with “de-novo synthesis”

• This hormonal effect occurred rapidly.

Role of c.AMP in Hormone Action▫ The cAMP plays an important role in the mechanism of action

of Protein Hormones.

▫ The Hormone (s) Insulin, Glucoagon, Catecholamine, Parathyroid Hormones show their effects by influencing the intracellular conc. of cAMP.

▫ The cAMP level is mediated through;▫ Tri-Meric NUcleotide-Regulatory Complex.

(Alpha-Beta-Gama subunits)▫ “α_GTP - Adenylate Cyclase system”

▫ The cAMP level increased with Glucagon (As αs_GTP complex activates adenylate cyclase) and decreased with insulin.(As αi_GTP complex in-activates adenylate cyclase)

Role of cGMP in Hormone Action▫ The cGMP plays an important role in the mechanism of

action of Growth Hormone

▫ The cGMP level is mediated through;▫ Tri-Meric NUcleotide-Regulatory Complex.

(Alpha-Beta-Gama subunits)▫ “α_GTP – Guanylate Cyclase system”

▫ The cGMP level is mediated through “αs_GTP – Guanylate Cyclase system” “αi_GTP – Guanylate Cyclase system”

Role of IP3 (Poly-Phosphoinositol) in Hormone Action.

▫The IP3 level is mediated through;

▫Tri-Meric NUcleotide-Regulatory Complex. and “α_GTP – Phospholipase C system”

The resultant IP3 causes mobilization of Ca++ from Cytosolic Resiviors e.g. R/E/R & Mitochondria.

Ca++ act as Tertiary Messenger.

Role of DAG (Di-acyl-glycerol) in Hormone action.

▫The DAG level is mediated through;

▫Tri-Meric NUcleotide-Regulatory Complex. and “α_GTP – Poly Phospho Inositol System”

The resultant DAG activates Ca++ Phosphatidyl Serine dependant Protein Kinase C, located inner cell Membrane

Ca++ act as Tertiary Messenger.

Role of Ca++ in Hormone action.

•Ca++ (The Third Messenger)▫Signaling for the Hormone action.▫Involve in Phospholipase A2. activity.▫Involve in Activation of Adenylate Cyclase

system for cAMP.▫Involve in Activation of Guanylate Cyclase

system for cGMP.▫Involve in “Ca++ Phosphatidyl Serine

dependant Protein Kinase C” for DAG.▫Glycogen Synthesis.

Role of Phosphorylation ofTyrosine Kinase in Hormone action.•Tyrosine Kinase coupled with

Insulin/Growth Hormone/Prolactin/Oxytocin.

•Phosphorylation of Tyrosine Residue of specific cellular proteins produce certain metabolic changes.

FACTORS REGULATING HORMONE ACTION.THE following are the factors influencing on hormone

action.

• Rate of synthesis and secretion.

• Circulatory pick up of the hormone.

• Hormones specific receptor/enzymes, differ from tissue to tissue.

• Ultimate degradation of the hormone (by liver/kidney)

REGULATION OF HORMONE SECRETION.•Hormone secretion is strictly under the

control of following mechanism (s).

▫The Neuro-Endocrinal Control Mechanism.▫The Feed-back Control Mechanism.▫The Endocrine Rhythms.▫The Ultradian Rhythm.

Hormone Transport in the Blood,

Water-soluble hormones (peptides and catecholamines are dissolved in the plasma and transported from their sites of synthesis to target tissues, where they diffuse out of the capillaries, into the interstitial fluid, and ultimately to target cells.

Steroid and thyroid hormones, in contrast, circulate in the blood mainly bound to plasma proteins. Usually less than 10 per cent of steroid or thyroid hormones in the plasma exist free in solution. For example, more than 99 per cent of the thyroxine in the blood is bound to plasma proteins. However, protein-bound hormones cannot easily diffuse across the capillaries and gain access to their target cells and are therefore biologically inactive until they dissociate from plasma proteins. ‘

• The relatively large amounts of hormones bound to proteins serve as reservoirs, replenishing the concentration of free hormones when they are bound to target receptors or lost from the circulation.

• Binding of hormones to plasma proteins greatly slows their clearance from the plasma

Hormone Transport in the Blood,

Hormone Metabolism and Excretion,• “Clearance” of Hormones from the Blood• Two factors can increase or decrease the concentration of a hormone in the blood.

▫ One of these is the rate of hormone secretion into the blood.

▫ The second is the rate of removal of the hormone from the blood, which is called

the metabolic clearance rate. ▫ This is usually expressed in terms of the number of milliliters of plasma cleared of

the hormone per minute.

• To calculate this clearance rate, one measures ▫ (1) the rate of disappearance of the hormone from the plasma per minute and ▫ (2) the concentration of the hormone in each milliliter of plasma. Then, the

metabolic clearance rate is calculated by the following formula:

• Metabolic clearance rate = Rate of disappearance of hormone from the plasma/Concentration of hormone in each milliliter of plasma

Hormone Metabolism and Excretion,• Hormones are “cleared” from the plasma in several• ways, including

▫ (1) metabolic destruction by the tissues, ▫ (2) binding with the tissues, ▫ (3) excretion by the liver into the bile, and ▫ (4) excretion by the kidneys into the urine.

▫ For certain hormones, a decreased metabolic clearance rate may cause an excessively high concentration of the hormone in the circulating body fluids.

▫ For instance, this occurs for several of the steroid hormones when the liver is diseased, because these hormones are conjugated mainly in the liver and then “cleared” into the bile.

Hormone Metabolism and Excretion,• Hormones are sometimes degraded at their target cells by enzymatic

processes that cause endocytosis of the cell membrane hormone-receptor complex; the hormone is then metabolized in the cell, and the receptors are usually recycled back to the cell membrane.

• Most of the peptide hormones and catecholamines are water soluble and circulate freely in the blood. They are usually degraded by enzymes in the blood and tissues and rapidly excreted by the kidneys and liver, thus remaining in the blood for only a short time.

• For example, the half-life of angiotensin II circulating in the blood is less than a minute.

• Hormones that are bound to plasma proteins are cleared from the blood at much slower rates and may remain in the circulation for several hours or even days.▫ The half-life of adrenal steroids in the circulation, for example, ranges between 20

and 100 minutes, whereas the half-life of the protein-bound thyroid hormones may be as long as 1 to 6 days

Hormone Metabolism (Thyroid Hormone)

Hypothalamus

Anterior pituitary Posterior pituitary

Thyrotropin

ACTH

Somatotropin

LH

FSHProlactin

Vasopressin

Oxytocin

ThyroidAdrenalCortex

AdrenalMedullaPancreas Ovary Testis

Muscles liver Tissues

Liver,muscles

EstradiolTestosteroneInsulin,glucagon,somatostatin

T3 Cortisolaldosterone

Mammary glands

Reproductive organs

Epinephrine

Releasinghormones

Nervous

Inputs that control Hormone Secretion

Control Systems Involving the Hypothalamus &Pituitary,

Feedback Loops

Rule: Hormones elicit their own shut off mechanismHypothalamus

Corticotropinreleasing factor

AnteriorPituitary

-Corticotropin

Cortisol

AdrenalCortex+

+

Control Systems Involving the Hypothalamus & Pituitary,

Candidate Hormones, type of Endocrine Disorders•Disease b/c Excess of Hormone;

▫Thyrotoxicosis

•Disease b/c Deficiency or depressed action of Hormone

▫Diabetes Mellitus

Diabetes Mellitus• Diabetes mellitus, arguably the most important

metabolic disease of man, is an insulin deficiency state. • Two principal forms of this disease are recognized:

• Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin.

• The onset of this disease typically is in childhood. It is due to destruction pancreatic B cells, most likely the result of autoimmunity to one or more components of those cells.

• Many of the acute effects of this disease can be controlled by insulin replacement therapy.

• Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.

Diabetes Mellitus (Conti)• Type II or non-insulin-dependent diabetes mellitus begins as

a syndrome of insulin resistance.

• That is, target tissues fail to respond appropriately to insulin.

• Typically, the onset of this disease is in adulthood.

• The nature of the defect has been evaluated - in some patients, the insulin receptor.

• In others, one or more aspects of insulin signaling is defective.

• In others, no defect has been identified. ▫ Either inability to secrete adequate amounts of insulin,

Insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents.

14.217.523%

15.622.544%

26.532.924%

1.01.3 33%

9.414.150%

World2000=151 million2010=221 million

2020 = 340 million Increase: 46%

84.5132.357%

Zimmet P et al. Nature. 2001;414:782.

Global Projectionsfor Diabetes 1995-2010

The Worsening Epidemicof Obesity and Diabetes

31% obese (BMI 30), increase from 23%

▫ 65% overweight (BMI 25), increase from 56%

▫ 4.7% extremely obese (BMI 40), increase from 2.9%

▫ No physical activity in 27%!▫ No regular activity in additional 28%▫ Each 1-kg increase in weight =

4.5%–9% increase in risk of diabetes

How can lifestyle changes be implemented long term?NHANES=National Health and Nutrition Examination Survey.

Normal

Type 2 Diabetes IRS/MS/XS Death

Courtesy of Wilfred Y. Fujimoto, MD.

Visceral Fat Distribution:Normal vs Type 2 Diabetes

INSULIN RESISTANCE SYNDROME

Insulin Resistance: Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of Hyperglycemiain Type 2 Diabetes

Insulin Resistance SyndromeThe Metabolic SyndromeThe X Syndrome.

• Hyper-insulinemia or excessive insulin secretion

• The Hyper-insulinemia is usually the result of an insulin-secreting tumor.

• This condition is much less common than diabetes mellitus.

• The high levels of insulin resulting from this condition

▫ May cause the overdose of insulin causes a precipitious drop in blood glucose concentrations.

▫ The brain becomes starved for energy, leading to the syndrome of insulin shock, which is acutely life-threatening. Death.

Metabolic Syndrome, Insulin Resistance, and Atherosclerosis

MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.

Hyperinsulinemia/hyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small, denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance