ENDOCRINOLOGY AND ENDOCRINE

PHYSIOLOGY- Overview

Anyakudo, Magnus Michael Chukwudike

(MBBS, M.Sc, Ph.D, FRHD, B.Th)
PIONEER HOD OF PHYSIOLOGY BUI 2008
PILLAR OF NATION BUILDING AWARDEE (SINRHD) 2013
FIRST NIGERIAN MEDICAL DOCTOR THAT BAGGED PhD IN PHYSIOLOGY FROM
UNIVERSITY OF IBADAN
PIONEER Ag. DEAN FACULTY OF BASIC MEDICAL SCIENCES UNIMED2015/2016
MEDICAL MISSIONARY (BLHC) CLERGY

Endocrinology/Metabolism, Reproductive,
Applied and Nutritional Health Researcher
Department of Physiology
UNIVERSITY OF MEDICAL SCIENCES (UNIMED)
ONDO, ONDO STATE
 LEARNING OUTCOMES/OUTLINE
At the end of this lecture, you would be made to
understand:
What endocrinology is all about
Endocrine system
Endocrine glands
Hormones
 Modern definition Vs Traditional definition
 Key concepts in hormone study
 Action/mediation
 Interactions
 Classifications
 Mechanisms of actions (signal transduction)
 Receptors
 Transducers
 Effectors
 Regulation/Control of hormone secretion 2
 DEFINITIONS
Endocrinology is the study of hormones, their receptors,
the intracellular signaling pathways and extracellular
communications they invoke, the diseases and the
conditions associated with them i.e. Pathophysiology of
endocrine disorders.
The term endocrine denotes biologically active substances
secreted internally to coordinate the physiology and
behavior of an animal by regulating, integrating, and
controlling its bodily functions.
Endocrinology is about communication systems &
information transfer.
Modern endocrinology
 Began in 20th century
 Claude Bernard (1813 – 1878)
 Walter Bradford Cannon (1871 – 1945)
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 Claude Bernard (1813 – 1878)
French physiologist
First to establish scientific methodology in medicine
Introduced experimental medicine and specifically
“blind studies” to ensure objectivity
Introduced “Milieu interieur” which was the initial
concept of homeostasis
 “The constancy of the internal environment is the condition for a
free and independent life”
 Disruption in the constancy leads to sickness
 Furthered in the next century by William Bradford Canon

4
 Walter Bradford Cannon (1871 – 1945)
American physiologist

Chaired the Department of Physiology at Harvard Medical School

Coined the concept of interior milieu as “Homeostasis’’

Also coined the term “fight or flight”

Did work with x-rays and different metals to improve x-ray quality of bowels
(today’s barium meal is a direct result)

Given credit for concept of homeostasis, published it in 1932

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 RESEARCH AREAS IN ENDOCRINOLOGY AND
METABOLISM
Research into endocrinology and metabolism touches
upon many of the most important health problems of our
time, including diabetes, obesity, hypertension,
osteoporosis and hormonal disturbances.
The research areas involve e.g.
nutrition,
physical activity,
anaesthesia and intensive care,
drug metabolism,
psychiatry,
neurology,
nephrology and
gastroenterology.
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 BRANCHES OF ENDOCRINOLOGY
Endocrinology has no strict definable anatomical borders like
other medical specialties. It pervades other specialties
Molecular endocrinology
Clinical endocrinology
Pediatric endocrinology
Geriatric endocrinology
Neuroendocrinology
Cardioendocrinology
Immunoendocrinology
Gastroenteroendocrinology
Nephroendocrinology
Hematoendocrinology. E.t.c
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 8
• The gut produces vast arrays of peptide hormones e.g. CCK, VIP, GIP, PP, gastrin, secretin,
motilin, somatostatin, neurotensin, peptide Y, enteroglucagon e.t.c. GASTROENTEROENDOCRINOLOGY:-
• clinical syndromes arise from excesssive amounts of these hormones e.g. Carcinoid, islet cell
tumour
• Erythropoietin synthesized in the kidney influences BM erythropoiesis
• Renin-angiotensin-aldosterone system involved in renal perfusion and BP regulation RENOHEMATOENDOCRINOLOGY:-
• The kidneys are primary target of several hormones such as PTH, mineralocorticoids and
vasopressin
• ANP (Atria natriuretic peptide) from the heart influences natriuresis on the kidney
CARDIOENDOCRINOLOGY:-
• Maintenance of BP, intravascular volume and PR in the CVS is achieved by some vital
hormones e.g. catecholamines ( NE, EP), angiotensin II, endothelin and NO
• Cortisol produced from adrenal cortex is a powerful immunosuppressant
• Some common endocrine diseases have an immunological basis e.g. autoimmune thyroid
IMMUNOENDOCRINOLOGY:-
disease, type 1 DM, Addison's disease, polyglandular failure
• Vast arrays of hormones (peptides) are produced in the brain (CNS, PNS)
• CNS via hypothalamic-RFs influences Pituitary hormones secretion
NEUROENDOCRINOLOGY:-
• PNS modulates adrenal medulla and pancreatic islet hormones production
Endocrinology has no strict definable anatomical borders like other medical specialties. It pervades other specialties
BRANCHES OF ENDOCRINOLOGY
 THE ENDOCRINE SYSTEM
 A diverse and complex system of endocrine glands and their
secretions involved in the coordination of various body
functions
 Possesses varied and sophisticated mechanisms that control
hormone synthesis, release, and activation, transport,
metabolism and delivery to the surface of target cells
 Principal function of the endocrine system is hormone
synthesis and secretion necessary for conveyance of
information between different cells and tissues, resulting in
regulation of many bodily functions.
 Hormones are secreted directly into the surrounding tissue fluid,
then taken up by blood and lymph capillaries, and transported
around the body.
 Exhibits complex relationships with the nervous, immune
and other systems (Basis of branches of endocrinology)
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 FUNCTIONS OF ENDOCRINE SYSTEM
Maintain Homeostasis
Plasma osmolality
Electrolytes
Total plasma volume

Support Cell Growth

differentiation
Fetal growth
Sexual differentiat

e adaptive
s to external Coordinate Developm
stress Physical maturatio
ies survival under adulthood
sful condition
Coordinate Reproduction and
parentingbehaviour
Physical
Olfactory (Pherohormone)
Visual 10
 MAINTENANCE OF HOMEOSTASIS

Virtually all hormones affect homeostasis:-

Thyroid hormone controls 25% of Basal
Metabolism in most tissues
Cortisol has direct effect as well as permissive
action for many other hormones
PTH regulates Ca2+ and PO43+ levels
Vasopressin regulates serum osmolality by
controlling renal free water clearance
Mineralocorticoids control vascular volumes
and serum electrolytes (esp Na+ and K+ )
concentrations
Insulin maintains euglycemia in fed and fasted
states 11
 GROWTH AND DIFFERENTIATION

Complex phenomenon of growth is mediated by

multiple hormones and nutritional factors.
GH, IGF-1 and thyroid hormone stimulates growth
whereas other hormones (sex steroids) lead to
epiphysial closure
Short stature may be caused by
GH deficiency
Hypothyroidism
Cushing’s syndrome
Precocious puberty
Malnutrition
Chronic illness
Genetic abnormalities affecting epiphysial growth plate
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 GROWTH AND DIFFERENTIATION
Short
Genetic stature may
abnormalities GH
be caused by
affecting epiphysial
growth plate
deficiency

Chronic Hypothyroid
illness ism

Malnutritio Cushing’s
n syndrome

Precocious
puberty
13
 REPRODUCTION
Endocrine system affects or influence various stages of
reproductive life from the fetus to senescence.
These include:
Stage of sex determination during fetal development
Stage of sexual maturation during puberty
Stage of conception, pregnancy, lactation and child bearing
Stage of cessation of reproductive capability at menopause

Multiple hormones interplay at various stages of

reproductive life

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REPRODUCTION

Multiple hormones
interplay at various
stages of
reproductive life

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TRADITIONAL CORE (ELEMENTS, COMPONENTS) OF
AN ENDOCRINE SYSTEM
Sender= Sending Cell
Response= Cellular (endocrine gland)
Response/physiologica
l action (2º Hormones)

Signal= Hormone
(secretion)

Effector=EffectorProtei
ns

Nondestructive
Medium= Serum
& Hormone
Binders (transport
medium)

Amplifier=
Transducer/EffectorEn
zymes

Selective Receiver=
Receptor Protein
(responding tissue)
Transducer=
Transducer Proteins
& 2º Messengers
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 ENDOCRINE GLAND
Definition : An endocrine gland is a group of
specialized cells with common origin in the
developing embryo and primarily concerned with
hormone secretion. Characteristically, classical
endocrine glands are ductless and highly
vascularized Many endocrine glands secret more
than one hormones e.g. Pituitary, Hypothalamus,
Pancreas etc.

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 CLASSIFICATIONS OF ENDOCRINE GLAND
Classical endocrine glands: parathyroid, thyroid,
hypothalamus, pituitary, pineal gland, adrenal,
endocrine pancreas, Gonads (testis and ovary)

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  Non-classical endocrine glands:


We now know that nearly every tissue secretes chemical signals that act as hormones:

Heart,

Immune cells,

Stomach,

Intestines,

Bone cells,

Liver,

Skin,

Adipocytes

Placenta

Glial cells, etc.

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EMBRYOGENESIS OF ENDOCRINE GLANDS
Embryonic digestive system:
 Thyroid
 pancreas

Embryonic nervous system

 Adrenal medulla
 parathyroid

Embryonic urogenital ridge

 Ovary
 Testes
 Adrenal cortex
Embryonic digestive and nervous system:
 Pituitary
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 HORMONES
Definition:
Chemical secretions from cells of ductless or
ductular glands (Not always from a gland) secreted
into the blood stream, lymph system or extracellular
fluid which influence the functions of neighboring
or distant cells of the same or different types.

Effective at very low concentration

Often measured in ng/ml
Hormones have an important role in the body's
metabolism, in salt and water balance, in the regulation of
blood pressure and temperature, in the formation of
bone, muscle, and blood, and in human reproduction.
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 Key concepts in hormone
1. For each hormone, what are the target cell and its receptor?
1. Single or multiple target cells
2. Single or multiple receptors
2. Site of hormone release and its pathway to target tissue?
1. Focal: Hypothalamus Pituitary
2. Global: Thyroid hormone Body
3. Effects of secretion, excretion and degradation on hormone levels?
1. Steady state (equilibrum)
2. Disequilibrum
4. Computational structures existing to control and regulate
hormonal levels?
1. Axis (linear control structure of series of cells each secretion stimulating the
subsequent cell)
2. Other control structures
5. Any other hormones acting on similar targets with similar effects?
1. Redundancy
2. Multiplicity
6. How do these different hormones affect body metabolism?

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 HORMONE ACTION/MEDIATION
Endocrine action: hormones secreted into blood and
affecting cells at distant sites (Traditional definition)
Paracrine action: the hormones are secreted into ECF and
acts locally by diffusing from its source to target cells of
different type in the neighborhood.
Autocrine action: the hormone are secreted into ECF and
acts locally on the same cell type that produced it.
Neuroendocrine action: synthesized in nerve endings
and released into blood circulation instead of synaptic cleft
(c.f neurotransmitter); interacts with receptors at distant
sites
Intracrine action: hormones released inside the cell (ICF)
and regulate intracellular events
Ectocrine : Ectocrine substances, such as pheromones, are
released into the environment to communicate with others.

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 HORMONAL INTERACTIONS
Synergistic (agonistic) effects: Two hormones work together
to produce a result just like when multiple drugs are taken (DDI).
 Additive:
 Each hormone separately produces response, together at same
concentrations stimulate even greater effect.
 Example: NE and Epi.

 Complementary:
 Each hormone stimulates different step in the process.
 E.g. FSH and testosterone.

Permissive effects:
 Hormone enhances the responsiveness of a target organ to second
hormone thus increasing the activity of a second hormone.
 E.g. Prior exposure of uterus to estrogen induces formation of receptors for
progesterone.
 Occurs especially during growth
 Hypothyroidism reduces the effects of steroid hormones

Antagonistic effects:
 Action of one hormone antagonizes the effects of another.
 Insulin and glucagon.
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 CLASSIFICATION OF HORMONES
Based on solubility:-
 The water soluble (polar) hormones are the catecholamines (epinephrine and
norepinephrine) and peptide/protein hormones. Half –life : short (minutes)
which varies with their molecular weights

 The lipid soluble (non polar or lipophilic) hormones include thyroid hormone,
steroid hormones and Vitamin D3 (Calcitriol). Half –life : long (hours, days)
which varies with the affinity of the hormone for protein carrier
Based on chemistry:-

 Proteins & peptides (most common)

 Lipids (steroids, eicosanoids)

 Amino acid derived (thyronines, dopamine, catecholamines)

 Gases (NO, CO)

 Vitamin derivatives (retinoids (Vit A) and calcitriol (Vit D)

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 PROTEIN AND POLYPEPTIDE HORMONES
 Examples –
 hormones of the anterior and posterior pituitary glands, the pancreas, parathyroid gland
and many others
 Description –
 Polypeptide hormones have chains of < 100 amino acids in length while protein hormones
have polypeptide chains with > 100 amino acids
 Water soluble
 Synthesis –
 In rough ER (as preprohormone and prohormone precursors which are inactive)
 In Golgi apparatus are packaged as active hormone following cleavage of precursor
hormone by cleavage enzyme
 Transport – dissolved in and transported by plasma unbound (free form)
 Storage – Secretory vesicle in the cytoplasm
 Secretion – achieved by mechanism of
 Increased Cytosolic Ca2+ conc . caused by memb. Depolarization
 Increased cAMP following receptor stimulation
 Protein Kinase activation
 Half – life - short (minutes) which varies with the molecular weight e.g. angiotensin II < 1
min.
 Clearance –
 usually degraded by enzymes in the blood and tissues and rapidly excreted by the
kidneys and liver. (reason for short T1/2) 26
 STEROID HORMONE
 Examples –
 Hormones of the adrenal cortex, ovaries, testes and the placenta
 Description –
 Lipid soluble
 Synthesis –
 From cholesterol (precursor)
 Storage –
 Usually not stored but readily synthesized when needed
 Transport –
 Bound (> 90%) with plasma transport (carrier) protein hence slows
clearance from blood. < 10% exists as free hormones
 Half – life –
 Half –life : long (hours, days) which varies with the affinity of the
hormone for protein carrier
 E.g. Adrenal steroids (20 – 100 mins); thyroid hormones 1 – 6 days
 Clearance –
 Slowly from the blood hence remain in circulation for hours – days
27
 EICOSANOIDS
Derivatives of arachidonic acid
Unsaturated FA
Produced by MANY cells
Unclear if hormone is the proper term
May be autocrine/paracrine, too
Produced by COX in response to cell damage
Mediators of inflammation
NSAIDS are COX inhibitors
Many other activities

28
 Examples –
Tyrosine or Tryptophan AMINO ACID DERIVATIVE HORMONES
 Hormones of thyroid glands and adrenal medullae
 Synthesis –
 From amino acid tyrosine or tryptophan in the cytoplasm
 Tryptophan Melatonin
 Tyrosine Catecholamines behave like peptide hormones
 Tyrosine Thyroid hormones behave like steroid hormones
 Description –
 Lipid soluble
 Storage –
 For thyroid hormones – thyroid follicle as thyroglobulin
 For adrenal medulla hormones – preformed vesicles
 Transport –
 Free (< 1 %)
 Bound (> 99 %) with plasma protein e.g. TBG
 Half – life –
 Half –life : long (hours, days) which varies with the affinity of the hormone for protein carrier
 Clearance –
 For thyroid hormones : behave like steroid hormones
 For adrenal medulla hormones: behave like peptide hormones
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Structures of amino acid derivative

30
 HORMONE CLEARANCE (HC)
This is the rate of removal of hormones from the blood also
called metabolic clearance rate (MCR).
Expressed in ml of plasma/min
Concentration of a hormone in blood is determined by 2
factors:
 Rate of secretion
 Rate of clearance
MCR = rate of disappearance of H from the plasma
Concentration of the H per ml of plasma
Measured using radioactive substance
Methods of clearance of H from plasma
 Metabolic destruction by tissues (sometimes at the target cells)
 Binding with tissues
 Excretion by liver into bile
 Excretion by kidney into urine
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 HORMONE RECEPTORS
Hormone Receptors are cellular proteins that bind
with high affinity to hormones & are altered in
shape & function by binding; they exist in limited
numbers.

Binding to hormone is noncovalent & reversible.

Hormone binding will alter binding to other

cellular proteins & may activate any receptor
protein enzyme actions.

32
 RECEPTOR TYPES
Membrane (surface) Receptors
 Imbedded in target cell membrane; integral proteins/
 glycoproteins; penetrate through membrane

 For protein & charged hormones (peptides or neurotransmitters)

 3 major groups:
 Serpentine = 7 transmembrane domains,
 Growth factor/cytokine = 1 transmembrane domain,
 Ion channels

Nuclear (intracellular) Receptors

 Nuclear proteins that act in pairs & bind to specific Hormone
Recognition Elements (HREs) = sequences on the DNA in the
promoter regions of target genes

 For small, hydrophobic molecules (steroids, thyroid hormones)

33
 INTRACELLULAR RECEPTORS
Steroid and thyroid hormones are lipophilic and
readily diffuse across cell membranes.
Their receptors are typically intracellular and are
classified according to their
cellular location,
dimerization and
the sequences of DNA to which they bind.
There is a large family of steroid receptors, all of which are
transcription factors. They bind to DNA and with other
transcription factors, initiate RNA synthesis.

34
CONTD

Receptors for the water soluble hormones are

found on the surface of the target cell, on the
plasma membrane.
 These types of receptors are coupled to various second
messenger systems which mediate the action of the
hormone in the target cell.

Receptors for the lipid soluble hormones reside in

the nucleus (and sometimes the cytoplasm) of the
target cell.
 Because these hormones can diffuse through the lipid
bilayer of the plasma membrane, their receptors are
located on the interior of the target cell 35
CELL SURFACE RECEPTOR ACTION

36
G-protein coupled receptors

37
38
 Transmembrane kinase-linked receptors
 Certain receptors have intrinsic kinase activity. These
include receptors for growth factors, insulin etc. Receptors
for growth factors usually have intrinsic tyrosine kinase
activity
 Other tyrosine-kinase associated receptor, such as those for
Growth Hormone, Prolactin and the cytokines, do not have
intrinsic kinase activity, but activate soluble, intracellular
kinases such as the Jak kinases.
 In addition, a newly described class of receptors have
intrinsic serine/threonine kinase activity—this class
includes receptors for inhibin, activin, TGFb, and
Mullerian Inhibitory Factor (MIF).

39
Protein tyrosine kinase receptors

40
Receptors for lipid-soluble hormones reside within the
cell
 Because these hormones can diffuse through the lipid bilayer of the
plasma membrane, their receptors are located on the interior of the
target cell.
 The lipid soluble hormone diffuses into the cell and binds to the
receptor which undergoes a conformational change. The receptor-
hormone complex is then binds to specific DNA sequences called
response elements.
 These DNA sequences are in the regulatory regions of genes.
 The receptor-hormone complex binds to the regulatory region of the
gene and changes the expression of that gene.
 In most cases binding of receptor-hormone complex to the gene
stimulating the transcription of messenger RNA.
 The messenger RNA travels to the cytoplasm where it is translated into
protein. The translated proteins that are produced participate in the
response that is evoked by the hormone in the target cell
 Responses evoked by lipid soluble hormones are usually SLOW,
requiring transcription/translation to evoke physiological
responses.
41
 HORMONES THAT BIND TO NUCLEAR RECEPTOR PROTEINS
 Lipophilic steroid and thyroid hormones are attached to
plasma carrier proteins.
 Hormones dissociate from carrier proteins to pass through lipid component
of the target plasma membrane.
 Receptors for the lipophilic hormones are known as nuclear
hormone receptors.
 Steroid receptors are located in cytoplasm and in the
nucleus.
 Function within cell to activate genetic transcription.
 Messenger RNA directs synthesis of specific enzyme proteins that change
metabolism.
 Each nuclear hormone receptor has 2 regions:
 A ligand (hormone)-binding domain.
 DNA-binding domain.
 Receptor must be activated by binding to hormone before
binding to specific region of DNA called HRE (hormone
responsive element).
 Located adjacent to gene that will be transcribed. 42
 Receptor control mechanisms
Hormonally induced negative regulation of receptors is
referred to as homologous-desensitization
This homeostatic mechanism protects from toxic effects of
hormone excess.
Heterologous desensitization occurs when exposure of the
cell to one agonist reduces the responsiveness of the cell
any other agonist that acts through a different receptor.
This most commonly occurs through receptors that act
through the adenylyl cyclase system.
Heterologous desensitization results in a broad pattern of
refractoriness with slower onset than homologous
desensitization

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 TRANSDUCERS
DEFINITION
Transducers are proteins that convert the information
carried by the hormones (signals) into chemical signals
(information) understood by cellular machinery (target
cells).
They change their shape & activity when they interact
directly with receptor (protein)-hormone complexes.
Are usually enzymes or nucleotide binding proteins
They produce 2nd messengers or change the activity of
other proteins by covalently modifying them by
 Adding or removing phosphate, lipid groups, acetate or
methyl groups or
 Interact with other proteins that do the addition or removal.

They begin the amplification of the energy content of the

original hormone signals.
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 EXAMPLES OF TRANSDUCERS

G – Proteins
Adenylyl Cyclase
Protein Kinase A
Phosphoinositides e.g. PLC
Protein Kinase C

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 G - PROTEIN
 Are guanosine triphosphate (GTP) – binding proteins that couple
hormone receptors to adjacent effector molecules
 E.g. in cAMP 2nd messenger system, G – protein couple the receptor to
adenylate cyclase
 Are also used in Ca 2+ - Calmodulin and IP3 2nd messenger systems
 Have intrinsic GTPase activity
 Have 3 subunits
 Αlpha
 Beta
 Gamma
 G –protein is either stimulatory (Gs) or inhibitory (Gi)
 Activity of stimulation or inhibition resides in the alpha subunit thus

can be depicted ( αs) or (αi)

 When α subunit is bound to GDP, it is inactive but become active when
bound to GTP

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47
48
49
 SECOND MESSENGER SYSTEMS

 Receptors for the water soluble hormones are found on the surface of
the target cell, on the plasma membrane. These types of receptors are
coupled to various second messenger systems which mediate the
action of the hormone in the target cell
 Types of second messenger systems: include
 Adenylate cyclase which catalyzes the conversion of ATP to cyclic
AMP;
 Guanylate cyclase which catalyzes the conversion of GMP to cyclic
GMP (cyclic AMP and cyclic GMP are known collectively as cyclic
nucleotides);
 Calcium and calmodulin;
 Phospholipase C which catalyzes phosphoinositide turnover
producing inositol phosphates and diacyl glycerol.
 The generation of second messengers and activation of specific protein
kinases results in changes in the activity of the target cell which
characterizes the response that the hormone evokes.
 Changes evoked by the actions of second messengers are usually rapid
50
 EFFECTORS
Effectors are the enzymes & other proteins that convert
the transduced hormonal signal into biochemical changes
that generate the cellular response to hormone binding.
Usually amplify the signal further & allow cellular work to
be done such as
 Cell motion

 Growth

 Cell division,

 Altered metabolism

 Secretion

 Depolarization, etc.

51
SIGNAL TRANSDUCTION: MECHANISMS OF HORMONE ACTION
Hormones of same chemical class have similar
mechanisms of action.
Similarities include:
 Location of cellular receptor proteins depends on the
chemical nature of the hormone.
 Events that occur in the target cells.

To respond to a hormone:

Target cell must have specific receptors for that
hormone (specificity).
 Hormones exhibit:
 Affinity (bind to receptors with high bond strength).
 Saturation (low capacity of receptors).

52
 MECHANISMS OF ACTION OF HORMONES /SECOND MESSENGERS
1. Cyclic AMP mechanism:
1. Examples of hormones utilizing this mechanism include:
ACTH, FSH/LH (Gonodotropins),TSH, ADH (V2
receptor), HCG, MSH, CRH, Calcitonin, PTH, Glucagon
2. IP3 (Inositol 1,4,5-triphosphate) mechanism:
1. E.g. :- GnRH, TRH,GHRH, Angiotensin II, ADH (V1 receptor),
oxytocin, CCK, Gastrin
3. Cyclic GMP mechanism:
1. E.g. :- ANP, EDRF (endothelium derived relaxing factor), Nitric
Oxide (NO)
4. Tyrosine kinase mechanism:
1. E.g. :- insulin, IGF-1, GH, Prolactin, EGF, PDGF, cytokines
5. Steroid/thyroid hormone mechanism:
1. E.g. :- steroid hormones: glucocorticoids, mineralocorticoids,
gonadal hormones, calcitriol (Vit. D)
2. Thyroid hormones: T4 and T3
53
54
Mechanism of lipid soluble hormone

55
 MECHANISMS OF STEROID HORMONE ACTION
Cytoplasmic receptor
binds to steroid hormone.
Translocates to nucleus.
DNA-binding domain
binds to specific HRE of
the DNA.
Dimerization occurs.
 Process of 2 receptor units
coming together at the 2
half-sites.
Stimulates transcription of
particular genes.

56
 Mechanism of Thyroid Hormone Action
 T4 passes into cytoplasm and is
converted to T3.
 Receptor proteins located in
nucleus.
 T binds to ligand-binding
3
domain.
 Other half-site is vitamin A
derivative (9-cis-retinoic) acid.
 DNA-binding domain can then
bind to the half-site of the HRE.
 Two partners can bind to the
DNA to activate HRE (hormone
responsive element).
 Stimulate transcription of genes.

57
Hormones That Use 2nd Messengers
Hormones cannot pass through plasma
membrane use 2nd messengers.
Catecholamine, polypeptide, and glycoprotein
hormones bind to receptor proteins on the target
plasma membrane.

Actions are mediated by 2nd messengers

(signal-transduction mechanisms).
 Extracellular hormones are transduced into intracellular
2nd messengers.

58
 ADENYLATE CYCLASE-cAMP
Polypeptide or glycoprotein hormone binds to receptor
protein causing dissociation of a subunit of G-protein.
G-protein subunit binds to and activates adenylate
cyclase.
ATP cAMP + PPi
cAMP attaches to inhibitory subunit of protein
kinase.
Inhibitory subunit dissociates and activates protein
kinase.

59
 Adenylate Cyclase-cAMP (continued)

 Phosphorylates enzymes within

the cell to produce hormone’s
effects.
 Modulates activity of enzymes
present in the cell.
 Alters metabolism of the cell.
 cAMP inactivated by
phosphodiesterase.
 Hydrolyzes cAMP to inactive
fragments.

60
 Phospholipase-C-Ca2+
Binding of Epi to a-adrenergic receptor in plasma
membrane activates a G-protein intermediate,
phospholipase C.
 Phospholipase C splits phospholipid into IP3 and DAG.
 Both derivatives serve as 2nd messengers.
IP3 diffuses through cytoplasm to ER.
 Binding of IP3 to receptor protein in ER causes Ca2+
channels to open.

61
 Phospholipase-C-Ca2+ (continued)

Ca2+ diffuses into the

cytoplasm.
 Ca2+ binds to calmodulin.
Calmodulin activates
specific protein kinase
enzymes.
 Alters the metabolism of the
cell, producing the
hormone’s effects.

62
Epinephrine Can Act Through Two 2nd
Messenger Systems

63
 Tyrosine Kinase
 Insulin receptor consists of 2 units that dimerize when they
bind with insulin.
 Insulin binds to ligand–binding site on plasma membrane,
activating enzymatic site in the cytoplasm.
 Autophosphorylation occurs, increasing tyrosine kinase
activity.
 Activates signaling molecules.
 Stimulate glycogen, fat and protein synthesis.
 Stimulate insertion of GLUT-4 carrier proteins.

64
Tyrosine Kinase (continued)

65
 BASIC CONTROL/REGULATION OF ENDOCRINE FUNCTION
2 major methods:
REGULATION OF HORMONE
SECRETION
 Classicalfeedback mechanisms
 negative and

 positive

 Local regulatory system

 autocrine and

 paracrine

REGULATION OF RECEPTORS
 Down regulation
 Up regulation
66
 FEEDBACK CONTROL
NEGATIVE FEEDBACK
Most commonly applied principle for regulating hormone
secretion
Self limiting
Directly or indirectly inhibits further secretion of the
hormone
Maintains hormone levels within a relatively narrow range
Examples:
 Thyroid hormones on the TRH-TSH axis
 Cortisol on the CRH-ACTH axis
 Gonadal steroids on the GnRH-LH/FSH
 IGF-1 on the GHRH-GH axis
 Endocrine systems that do not involved pituitary gland e.g. Ca2+
feedback on PTH, glucose inhibition of insulin secretion, leptin
feedback on the hypothalamus etc.

67
POSITIVE FEEDBACK
Rare not very well understood
Explosive and self re-enforcing
Directly or indirectly cause more secretion of the hormone
(10 to 20 fold amplification )
E.g. estrogen mediated stimulation of the mid cycle LH
surge
Just before ovulation, LH surge occurs secondary to the
positive feedback of estrogen on the anterior pituitary
LH acts on the ovaries to produce more estrogen
 NB: chronic low level of estrogen actually inhibit the ant.
Pituitary but gradually rising level of estrogen stimulates LH
secretion probably by:
1. Activation of the hypothalamic GnRH pulse generator or
2. Extraordinary sensitivity of E2 – primed gonadotropes to GnRH

68
 LOCAL REGULATORY SYSTEM
Often involves growth factors
Becoming increasingly recognized
Are difficult to document like classical endocrine
action due to the fact that concentrations of the
local growth factor are not readily measured
A. PARACRINE REGULATION
• Hormones act on adjacent cells
• Factors released by one cell acts on an adjacent cell in the same tissue
• E.g. somatostatin secretion by the pancreatic δ cells inhibits secretion
from nearby β cells
B. AUTOCRINE REGULATION
 Hormone acts back on the cell of origin
 IGF-1 acts on many cells that produce it such as : chondrocytes, breast
epithelium, gonadal cells

69
 REGULATION OF RECEPTORS
 Another major method of control of endocrine function
 Sensitivity of the target tissue is determined by the hormone by:
 Regulating the number of binding receptors or
 Altering the sensitivity of the receptors

 DOWN - REGULATION
 A hormone decreases the number or affinity of receptors for itself or for
another hormone
 E.g. progesterone down regulates its own receptors and receptors for
estrogen in the uterus

 UP – REGULATION
 A hormone increases the number or affinity of receptors for itself or for
another hormone
 E.g. estrogen up - regulates its own receptors and receptors for LH in the
ovary

70
ENDOCRINOLOGY: We have the best people in it.
CRITICAL THINKING AND EVALUATION 71
Rev. Dr. Anyakudo, Magnus Michael Chukwudike
(MBBS, M.Sc, Ph.D, FRHD, B.Th)

(TO GOD BE THE GLORY)

FOR EXCELLENCE AND TRUTH THROUGH HARDWORK 72

ENDOCRINOLOGY AND ENDOCRINE PHYSIOLOGY-
Overview
M. M. C. Anyakudo

University of Medical Sciences ,Ondo State