This document discusses molecular endocrinology and hormones. It defines endocrinology, describes the major endocrine glands and hormones, and explains hormone structure, synthesis, mechanisms of action, transport, and regulation. Key points include that hormones act as chemical messengers to modify distant organ functions, are produced in one part of the body and carried via circulation to target tissues, and include proteins, peptides, amino acid derivatives, and steroids.
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Hormone new 1 (2)
1.
2. 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.
3. 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.
6. 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.
8. HORMONE
PROTEIN/PEPTIDE
• These are either large protein molecules or
medium/small sized peptides.
• Insulin & Glucagon
• Parathrombin & Calcitonine
• Pituitary Hormones.
9. HORMONE
AMINO 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
10. HORMONE
STEROIDS
• These are Steroid in nature such as;
• Adrenocorticoid Hormones,
• Androgens.
• Estrogens.
• Progesterone.
11. 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.
12. 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
Physiology
11th ed,
Guyton & Hall
Ch 74,
Pg No 915
IP3= Inositol Triphosphate
DAG = DiAcyl Glycerol
AA = Archidonic Acid.
Recognition &
Hormone
Release
Signal Generation
Biological Effects.
13. 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 Physiology
11th, Guyton & Hall
Ch 74, Pg No 913
cAMP = Cytoplasmic Adenosine Mono-phosphate.
14. Mechanism of Action for lipid-soluble or steroid Endocrine hormones
Lipid-Soluble Hormones Aldosterone Calcitriol Testosterone Estrogen
Progesterone T3 & T4
16. 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 Messenger
Drugs (Chemical Agents/Biological Agents)
17. Interacting with Surface Receptor.
Types of Receptor (s)
RECEPTORS
LIGAND GATED ION CHANNELS/IONOTROPIC
G-PROTEIN COUPLED /METABOTROPIC
KINASE LINKED
NUCLEAR
18. 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.
19. 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)
20. 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).
21. 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.
22. 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)
23. 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”
24. 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.
25. 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.
26. 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.
27. Role of Phosphorylation of
Tyrosine 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.
28. 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)
29. 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.
30. 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
32. 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
33. 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.
34. 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
39. Candidate Hormones,
type of Endocrine Disorders
• Disease b/c Excess of Hormone;
▫ Thyrotoxicosis
• Disease b/c Deficiency or depressed action of
Hormone
▫ Diabetes Mellitus
40. 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.
41. 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.
43. The Worsening Epidemic
of 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.
44. Normal
Type 2 Diabetes IRS/MS/XS Death
Courtesy of Wilfred Y. Fujimoto, MD.
Visceral Fat Distribution:
Normal vs Type 2 Diabetes
46. Insulin Resistance: Receptor and Postreceptor Defects
Peripheral tissues
(skeletal muscle)
Increased glucose
Pancreas
Liver
Impaired insulin secretion
Increased glucose
production
X
Insufficient glucose
disposal
Causes of Hyperglycemia
in Type 2 Diabetes
47. Insulin Resistance Syndrome
The Metabolic Syndrome
The 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.
48. Metabolic Syndrome, Insulin Resistance, and Atherosclerosis
MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.
Hyperinsulinemia/hyperproinsulinemia
Glucose
intolerance
Increased
triglycerides
Decreased
HDL cholesterol
Increased BP
Endothelial dysfunction
Small, dense
LDL
Atherosclerotic
cardiovascular
disease
Increased
PAI-1
Insulin resistance
