CLINICAL ENDOCRINOLOGY
OBJECTIVES:
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14.
Explain why the endocrine system is so closely related to the nervous system.
Distinguish between an endocrine gland and an exocrine gland.
Define the term hormone and explain its general characteristics.
Distinguish between a steroidal and non-steroidal hormone, in terms of
composition and action.
For each of the glands, name the hormone(s) they secrete, identify the
target organ of each hormone, and the effect of each hormone.
Define the term gonadotropin, name of hormones secreted by the pituitary
,thyroid,adrenal glands,pancreatic gonadal gland ….
Distinguish between dwarfism, giantism, and acromegaly
Describe how calcium levels are maintained in the blood.
The hormones that work together to regulate water and electrolyte levels in
the blood and therefore regulate blood pressure.
Describe how glucose levels are maintained in the blood.
Compare and contrast cretinism, myxedema, Grave’s Disease, and goiter.
Define the blood ,stimulatory tests, and other diagnostic procedures to
define the disease.
To describe secondary sexual characteristics ,differentiate between virilism
and hirsutism, get information about PCOS and ovulatory cycle.
Describe the adipose tissue -derived hormones ( leptin,adiponectin,resistin)
and their role in adiposity
Learning outcomes
1. List the cells and state the hormones secreted by
anterior and posterior pituitary,thyroid
gland,adrenal,pancreas, gonads
2. Explain the role of hypothalamus in controlling
anterior & posterior pituitary
3. Describe the regulation of secretion & actions of
different hormones
4. Explain the neural control of hormone release.
5. Describe specific hormonal disorders
6. Describe the role of adipose tissue in regulation
of body metabolism
Nervous and Endocrine Systems
• Act together to coordinate functions of all body systems
• Nervous system
– Nerve impulses/ Neurotransmitters
– Faster responses, briefer effects, acts on specific target
• Endocrine system Composed of endocrine glands
produce, store, and secrete hormones.
that
– HORMONE = a very powerful chemical substance
secreted by an endocrine gland into the bloodstream,
that affects the function of another cell or "target cell
Types of Glands
Exocrine Glands are those which release their cellular
secretions through a duct which empties to the outside or
into the lumen (empty internal space) of an organ. These
include certain sweat glands, salivary and pancreatic glands,
and mammary glands. They are not considered a part of the
endocrine system.
Endocrine Glands are those glands which have no duct and
release their secretions directly into the intercellular fluid or
into the blood. The collection of endocrine glands makes up
the endocrine system.The main endocrine glands are :
pituitary (anterior and posterior lobes)
thyroid, parathyroid - `
Adrenal (cortex and medulla)
pancreas and gonads
• Hormone types
– Circulating –
circulate in blood
throughout body
– Local hormones –
act locally
• PARACRINE –
act on
neighboring cells
• AUTOCRINE –
act on the same
cell that
secreted them
General characteristic of hormones
1. needed in very small amounts (potent);
2. produce long-lasting effects in the cells they target;
3. regulate metabolic processes (maintain homeostasis)
4. may be steroid (produced from cholesterol = fat-soluble) or
non-steroid (water-soluble).
5. they have specific rates and patterns of secretion (diurnal,
pulsatile, cyclic patterns, pattern that depends on the level of
circulating substrates)
6. they operate within feedback systems, either positive(rare) or
negative, to maintain an optimal internal environment
7. they affect only cells with appropriate receptors  specific
cell function(s) is initiated
8. they are excreted by the kidney, deactivated by the liver or by
other mechanisms
Some general effects of hormones
Hormones regulate the transport of ions,
substrates and metabolites across the
cell membrane:
1. they stimulate transport of glucose and
amino acids
2. they influence of ionic transport across the
cell membrane
3. they influence of epithelial transporting
mechanisms
4. they stimulate or inhibit of cellular enzymes
5. they influence the cells genetic information
Control of Hormone Secretion
Control of secretion is in the form of neural, hormonal, or humoral stimuli.
1. Neural: Signals from nervous system
The adrenal medulla is directly stimulated by the sympathetic nervous
system. Epinephrine and NE reinforce the actions of the sympathetic
nervous system.
2. Hormonal
Occurs when hormones from one endocrine gland stimulate the secretion of
hormones from another endocrine gland.
E.g. TRH,TSH, TH
E.g. CRH, ACTH,Cortisol
These routes of secretion are usually controlled in a negative feedback manner.
3. Humoral : Chemical changes in the blood
Occurs when substances other than hormones control the secretion of
endocrine glands.
E.g. Insulin secretion by the pancreas is determined by several factors.
Rise in glucose after a meal triggers insulin secretion.
Rise in amino acids after a meal triggers insulin secretion.
In addition hormonal and neural stimuli also play a role in insulin secretion.
or change in osmolarity (ADH release)
Chemical classes of hormones
1. Amino acid-derived: Hormones that are modified amino acids (catecholamines,
thyroid hormones, prostaglandins, leucotrienes, dopamine, serotonine, GABA,
melatonin)
2. Polypeptide and proteins: Hormones that are chains of amino acids of less than
or more than about 100 amino acids, respectively. Some protein hormones are
actually glycoproteins, containing glucose or other carbohydrate groups. (insulin,
GH, Leptin...)
3. Steroids: Hormones that are lipids synthesized from cholesterol. Steroids are
characterized by four interlocking carbohydrate rings.(a) Corticoids (cortisol,
aldosterone,, b) sex hormones(androgen,estrogen, progesterone),c) Nitric oxide
(NO)
4. Eicosanoids: Are lipids synthesized from the fatty acid chains of phospholipids
found in plasma membrane.
Hormones circulating in the blood diffuse into the interstitial fluids surrounding
the cell. Cells with specific receptors for a hormone respond with an action that is
appropriate for the cell. Because of the specificity of hormone and target
cell, the effects produced by a single hormone may vary among different kinds of
target cells.
Another groups of hormones
A. gastrointestinal hormones (more than 26 GI polypeptides)
B. opioid peptides (endogenic opioids)
C. tissue growth factors (epidermal growth factor, nerve growth factor,
PDGF, insuline-like growth factor ...)
D. atrial natriuretic hormone (ANF)
E. transforming growth factors and hematopoietic
and other growth factors (FGF....)
F. endothelial factors (endothelins, EDRF...)
G. cytokines (interleukiny, interferón, TNF....)
Hormones activate target cells by one of two methods,
depending upon the chemical nature of the hormone.
• Lipid-soluble hormones (steroid hormones and
hormones of the thyroid gland) diffuse through the cell
membranes of target cells. The lipid-soluble hormone
then binds to a receptor protein that, in turn, activates a
DNA segment that turns on specific genes. The proteins
produced as result of the transcription of the genes and
subsequent translation of mRNA act as enzymes that
regulate specific physiological cell activity.
•Lipid-soluble hormones are bound to plasma proteins
and are less easily metabolized and excreted from the
body.
E.g. TH has a half-life of several days.
E.g. Cortisol has a half-life of about 90 minutes
Blood capillary
Free hormone
1 Lipid-soluble
1 Lipid-soluble
Transport
protein
Transport
protein
hormone
hormone
diffuses
diffuses
into cell
into cell
Activated 2 Activated
receptor-hormone
receptor-hormone
complex alterscomplex alters
gene expression
gene expression
2
Nucleus
Nucleus
Receptor
Receptor
DNA
DNA
Cytosol
3
Cytosol
3 Newly formed
Newly formed
mRNA directs mRNA directs
synthesis of synthesis of
specific proteins
specific proteins
on ribosomes on ribosomes
mRNA
mRNA
Ribosome
Ribosome
New
protein
4 New proteins alter
cell's activity
Target cell
Lipidsoluble
Water-soluble hormones (polypeptide, protein, and
most amino acid hormones) bind to a receptor
protein on the plasma membrane of the cell. The
receptor protein, in turn, stimulates the production of
one of chemical messengers.
- Water-soluble hormones are easily degraded by
enzymes in the blood stream and are also excreted very
quickly from the kidneys.
E.g. insulin has a half-life of about 10 minutes in the
body.
E.g. Epinephrine has a half-life of about 10 seconds
in the body.
Blood capillary
Blood capillary
Binding(first
of hormone
messenger)
(first messenger)
1 Binding of1 hormone
Watersoluble
Hormones
to its receptorto
activates
its receptor
G protein,
activates G protein,
which activates
which
adenylate
activates
cyclase
adenylate cyclase
Water-soluble
hormone
Adenylate cyclase Adenylate cyclase
Receptor
Second messenger
G protein
G protein
ATP
ATP cAMP
Second messenger
2 Activated
cAMP adenylate 2
Activated adenylate
cyclase converts
ATP to cAMP
cyclase converts
ATP to cAMP
6
Protein
Protein
kinases
kinases
serves
serves
as a as a
3 cAMP
3 cAMP
Activated
second
second
messenger
messenger protein
to activate
to activate
protein
protein kinases
kinases
kinases
Protein
Protein
Activated
protein
kinases
4 Activated protein
ATP
kinases
phosphorylate
ATP cellular proteins
ADP
ADP
Protein— Protein—
P
P
Millions of phosphorylated
5 Millions5 of phosphorylated
proteins cause
proteins
reactions
cause
that
reactions that
produce physiological
produce physiological
responses responses
Target cell
Phosphodiesterase
inactivates cAMP
4
Activated protein
kinases
phosphorylate
cellular proteins
second messengers: The small molecule generated inside
cells in response to binding of hormone or other mediator
to cell surface receptors
• Calcium (Ca2+)
– Target: calmodulin
– Calmodulin  protein kinases
• Cyclic nucleotides
– cAMP & cGMP
– Target: protein kinases
• Diacylglycerol (DAG) & IP3
– Phosphoipase C act on the PIP2 From membrane lipids
– DAG  Protein Kinase C (membrane)
– IP3  Ca2+ (triggers the release of Ca2+from the
endoplasmic reticulum, which then activates
enzymes that generate cellular changes.)
RECEPTORS: General Characteristics of
Receptors
• Receptors bind hormones, resulting in a biological
response
• All receptors exhibit general characteristics:
1. Specific Binding (structural and steric
specificity)
2. High Affinity (at physiological concentrations)
3. Saturation (limited, finite # of binding sites)
4. Signal Transduction (early chem event must
occur)
5. Cell Specificity (in accordance with target organ
specificity).
All receptors have two functional domains:
Recognition domain: it binds the hormone
2. Coupling domain: it generates a signal that
couples the hormone recognition to some
intracellular function.
 Coupling means signal transduction.
 Receptors are proteins.
1.
 They are present in
cell membranes
Intracellular receptors:
cytoplasmic receptors
nuclear receptors
Cell Surface (membrane)Receptors
 There are three types of cell surface
receptors:
1. Ion channel receptors :Ionotropic
1. Transmembrane receptors: G-proteincoupled receptors,Metabotropic
 Receptors that are kinases or bind
kinases: Protein kinases  phosphorylation
Neurotrophins
Cell surface receptors: G- protein receptors
A.
a.
b.
c.
d.
Basic G-protein Receptor
ligand binds to receptor (outer surface of cell).
receptor changes shape (inner surface of cell). shape
change allows receptor to bind inactive G-protein
inactive G-protein binds to receptor
receptor activates G-protein
a. G-alpha drops GDP, picks up GTP
b. when G-alpha binds GTP --> G-beta and G-gamma are released
c. G-alpha + GTP is released from receptor into cytoplasm
d. G-alpha + GTP = active G-protein.
e. activated G-protein binds to target protein target protein's activity
is altered - might be stimulated or might be inhibited .
f. G-alpha + GTP is released from receptor into cytoplasm
g. G-alpha + GTP = active G-protein.
h. The G protein activates adenylate cyclase, the enzyme that
catalyzes the production of cAMP from ATP.Cyclic AMP then
triggers an enzyme that generates specific cellular changes - might
be stimulated or might be inhibited .
Intracellular Receptors
• Some receptor proteins are intracellular, found in
the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers (1st
messenger,I,e hormone) can readily cross the
membrane and activate receptors
• Examples of hydrophobic messengers are the
steroid and thyroid hormones of animals
• An activated hormone-receptor complex can act
as a transcription factor, turning on specific
genes
 The action of nuclear receptors is slow, as it
takes some hours for the whole process to
occur. The effect is long-lasting (or even
permanent) and changes the properties of
the cell. This type of process is important in
development, differentiation and maturation
of cells, e.g. gametes (eggs and sperm cells).
 Transcriptional activator proteins
 DNA  RNA  Proteins
Steroid Hormones
 Steroid hormones are lipid soluble.
 Steroids can diffuse through the membrane
1. Diffuse through the membrane
2. Binds & activates intracellular receptor.
 3. Steroid-Receptor complex then enters the nucleus and
binds to a particular sequence on the DNA which is called
hormone response element (HRE).
4. Activates a gene.
5. Gene transcribed into messenger RNA.
6. mRNA goes to the ribosomes
7. Translate mRNA into protein
 Thyroid and Retinoids go directly into the
nucleus.
 Their receptor is already bound to HRE, but
along with a co –repressor protein which fails
to activate transcription.
 The association of the ligand with the
receptor results in the dissociation of the co
repressor.
 Now this receptor- ligand complex can bind
other co activator proteins and transcription
begins.
Negative Feedback in the Hypothalamus.
• Most hormonal regulation by negative feedback
– Few examples of positive feedback
• hypothalamus maintains fairly constant levels of hormones
because it operates The a negative feedback system. E.g:
excitatory
Hypothalamus
Thyroid Stimulating Hormone-Releasing
Hormone
inhibitory
Anterior pituitary
Thyroid Stimulating Hormone
Thyroid gland
Thyroid hormones
• positive feedback. In such a system, hormones cause a
condition to intensify, rather than decrease. As the condition
intensifies, hormone production increases. Such positive
feedback is uncommon, but does occur during childbirth,
where hormone levels build with increasingly intense labor
contractions. Also in lactation, hormone levels increase in
response to nursing, which causes an increase in milk
production. The hormone produced by the hypothalamus
causing the milk let down and uterine contraction is oxytocin.
A classic example is the production of estrogen in
response to gonadotropins. The consequences (or the
outcome ) of increased estrogen production are the
further production of gonadotropins, thus promoting
more estrogen production.
Mechanisms of hormonal alterations
Endocrine diseases
A. elevated hormones level
B. depressed hormones level
Hormone excess
Hormone deficiency
Hormone resistance
may be caused by:
1. failure of feedback systems
2. dysfunction of endocrine gland or endocrine function of cells:
a) secretory cells are unable to produce or do not obtain
an adequate quantity of required hormone precursors
b) secretory cells are unable to convert the precursors to the
appropriate active form of hormon
c) secretory cells may synthesize and release excessive amounts
of hormone
3. degradation of hormones at an altered rate or they may be
inactivated by antibodies before reaching the target cell
4. ectopic sources of hormones
C. failure of the target cells to respond to hormone
May be caused by:
1. receptor-associated disorders:
a. decrease in the number of receptors   hormone - receptor binding
b. impaired receptor function  sensitivity to the hormone
c. antibodies against specific receptors
d. unusual expression of receptor function
2. intracellular disorders:a) inadequate synthesis of the second messengers
b) number of intracellular receptors may be decreased or they may
have altered affinity for hormones
c) alterations in generation of new messenger RNA or absence of
substrates for new protein synthesis
Primary & secondary endocrine diseases
Based on site of hormone defect (either increase or
decreased secretion), Endocrine disorders are classified
as:
• A) Primary Disease: If defect is in the target gland from
which hormone has originated
• B) Secondary Disease: If defect is in the Anterior Pituitary
or Hypothalamus
E.g.,
• Primary hypothyroidism means decreased secretion of
thyroid hormone from the Thyroid gland
• Secondary hypothyroidism means deficiency of Anterior
pituitary/ Hypothalamic hormone which stimulates
production of thyroid hormone from the thyroid gland
(defect not in the thyroid gland)
Investigations for Endocine Disorders
I.
Basal hormonal concentrations
1. Basal plasma levels (one-time examination)
2. Diurnal dynamics of hormone concentrations (e.g.
cortisol,growth H)
3. Other hormonal cycles (e.g. menstrual phase dynamics:
cyclic changes of LH, FSH, estrogens and progesteron)
4. Urinary output: 24 hr Is alternative method for hormones
with diurnal dynamics (cortisol, aldosterone) or pulsate
secretion (catecholamines),
5. Hormonal metabolites - plasma, urine (e.g. C-peptide), 5HIAA (hydroxyindole acetic acid),Serotonin metabolite
Urinary excretion measurement in patients with suspicious
carcinoid.
6. Indirect evaluation - measurement of a metabolic response
(ADH ... diuresis, insulin ... glycaemia etc.)
II. Functional tests
Functional tests:1. Inhibitory tests
2. Stimulatory tests
Basal hormonal concentration very often doesn´t allow to
establish a diagnosis of hypo- or hyperfunction.
Suspect hypofunction  Stimulatory tests
= quantification of functional reserve of endocrine gland,
Insulin hypoglycemia test, Arginin infusion test,TRH test
GnRH test,CRH test
Suspect hyperfunction  Inhibitory tests
= quantification of responsibility of endocrine gland to
inhibitory factors, e.g. Dexamethazone test, Dopaminergic
drugs test
Principles:
• negative feedback inhibition / stimulation
• direct stimulation / inhibition
Tumor markers in endocrinology
Thyroglobulin (Tg), anti-Tg antibodies
Markers of non-medullar thyroid carcinoma.
CEA (carcinoembryonic antigen)
Marker of non-medullar thyroid carcinoma (and ather malignancy – e.g.
colorectal ca)
Diagnostic usage in combination with Tg and anti-Tg Ab
Calcitonin, procalcitonin
Hormonal product and diagnostic marker of medullar thyroid
carcinoma (lower sensitivity that Tg for non-medullar thyroid ca)
newborn screening :
1. Congenital hypothyroidism - incidence 1 : 5000
screening based on elevation of TSH
2. Congenital adrenal hyperplasia (CAH) - incidence 1 : 10-14000
screening based on elevation of 17-OH-progesterone
3. Phenylketonuria
Imaging methods
Indications:
A. Localization of endocrine active tumors, hyperplasia, ectopic
hormonal production
B. Evaluation of systemic complications
1. Native X-ray exams
2. Ultrasonography
3. CT / MRI
4. Scintigraphy
5. Angiography
Biopsy
Thyroid gland - unclear solitary nodule, tumors
2. Adrenal glands - rarely
Thyroid gland - Fine needle aspiration biopsy (FNAB)