PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULE
CHAPTER 1
Mechanisms of Hormone Action
Samuel Dagogo-Jack, M.D.
Monday, November 30, 2009, 8:00-8:50am
Objectives:
1.
Define hormone and various forms of cellular communication (i.e., endocrine,
paracrine, autocrine and juxtacrine) and endocrine rhythm.
2.
Classify major hormones, their glandular source and their types.
3.
Distinguish between the two classes of hormones, their characteristics, and site
of action on target tissue.
4.
Recognize various forms of hormone receptor-interaction and mechanisms of
hormone action.
5.
Define general principle of peptide hormone synthesis.
6.
Explain negative and positive feedback in hormone physiology.
7.
Assess various methodologies of hormone measurement and endocrine function
tests.
8.
Cite general classification of endocrine disorders.
9.
Relate possible mechanisms of hormone resistant states.
10.
Understand new concept on the role of fat tissue as a major endocrine organ.
OVERVIEW
Introduction
Study of the pathophysiology of endocrine disorders requires basic knowledge of
endocrine anatomy, physiology, and biochemistry, as well as pathology.
In this course we assume adequate knowledge of the anatomy, physiology, and
biochemistry of the endocrine glands. However, a brief review of the major concepts
will be made to better understand the pathophysiology.
Mechanisms of Hormone Action
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As each major topic in the endocrine module will be prefaced by a review of the basic
principles, this overview will not deal with individual glands, but rather it will emphasize
the general principles of endocrine gland physiology and assessment of their functions.
DEFINITION OF HORMONE
The term “hormone” was introduced by Starling in 1905. It is derived from the Greek
meaning “to arouse”. Hormones are chemicals that are produced by “ductless” glands,
secreted into circulation in nanomolar concentrations and affect target tissues away
from the site of their secretion.
_____________________________________________________________________
TABLE 1
Concentration of Hormones in the Body (Compared to Glucose and K+)
_____________________________________________________________________
Plasma Concentration
Pancreas
(10-9 M)
Insulin
Glucagon
1
20
Adrenal
Cortisol
Epinephrine
300
5
Plasma Glucose or K+
5,000,000
_____________________________________________________________________
Various Forms of Cellular Communications
Endocrine:
“Transmitter” reaches the target tissue through circulation, e.g.,
ACTH stimulates cortisol production in adrenal.
Paracrine:
“Transmitter” reaches the target tissue in the vicinity of its
secretion, e.g., Angiotensin II in the kidney.
Juxtacrine:
“Transmitter” in membrane of one cell can interact with receptor of
a cell next to it, e.g., hematopoietic growth factor.
Autocrine:
“Transmitter” can act on the same cell that released it, e.g., Insulin
from β cell can inhibit its own secretions.
Mechanisms of Hormone Action
1-2
Figure 1
Targ et cell
Targ et Cell
H
H
H
Autocrine
Endocrine
Paracrine
Neuron
Neuron
Neuroendocrine
Neurotransm itter
Targ et Cell
Endocrine Rhythm
Essentially all hormones are secreted in rhythmic and cyclic pattern. These patterns
may have various controlling mechanisms such as light, deep sleep or awakening and
other external causes. There are three types of rhythm.
1.
2.
3.
Circadian - 24 hour cycle
Ultradian - shorter than 24 hour cycle
Infradian - longer than 24 hour cycle (i.e. menstrual cycle in women)
Mechanisms of Hormone Action
1-3
TABLE 2
The Major Endocrine Glands and Their Characteristic Hormones
_____________________________________________________________________
Structural
Gland
Hormone
Characteristics
Hypothalamus
and median
eminence
Anterior Pituitary
TRH
Somatostatin
GNRH
CRH
GHRH
Prolactin-inhibiting factor
(dopamine)
Peptide
Biogenic amine
TSH
LH
FSH
Glycoprotein
GH
Prolactin
ACTH
Protein
ADH
(Vasopressin)
Oxytocin
Peptide
Thyroid
T4, T3
Calcitonin
Tyrosine derivatives
Peptide
Parathyroid
PTH
Peptide
Adrenal Cortex
Aldosterone, Cortisol
Androgens and estrogens
Steroids
Adrenal Medulla
Epinephrine and Norepinephrine
Catecholamines
Stomach
Gastrin
GLP-1
Peptide
Peptide
Pancreas (islets of
Langerhans)
Glucagon (α cell)
Insulin (β cell)
Somatostatin (D cell)
Pancreatic polypeptide (F cell)
Amylin
Duodenum and
jejunum
Secretin
Cholecystokinin
Protein
Ovary
Estrogen, progesterone
Steroid
Testis
Testosterone
Steroid
Fat tissue
Adipokines
protein & cytokines
Posterior Pituitary
Mechanisms of Hormone Action
Protein
1-4
Fat Tissue as a Major Endocrine Gland
Although in previous years it was assumed that fat tissue, similar to bone, is not an active
tissue, subsequent works have proven that both concepts about bone and fat tissue were
wrong. It is now believed that fat tissue is an important endocrine organ and produces
many compounds which play important roles in the body’s metabolic balance, which will be
discussed in more detail (Chapter 5) Figure 2 provides the latest information on all the
chemicals that are produced by fat cells, which are collectively call “adipokines”. Some of
these are hormones; others are cytokines, some of which are important cardiovascular risk
factors and are associated with insulin resistance (i.e. TNFα, IL6, Resistin, CRP, FFA, &
PAI-1).
Adipokines
Visfatin is a newly discovered hormone isolated from fat tissue and has insulin-like activity
(Science 307:366-7, 2005)
Hormonal Classification
In general, endocrine glands secrete one of two types of hormones in the circulation.
These could be classified as (a) polypeptide hormones (and catecholamines), and (b)
steroid hormones (and thyroid hormones). Each class has special characteristics which
are summarized in the accompanying table.
Mechanisms of Hormone Action
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TABLE 3
General Classification of Hormones
Properties
Polypeptides
Steroids
MOLECULAR WEIGHT
Large (i.e., >500)
Small (i.e., <500)
TIME OF ACTION
Fast (minutes)
Slow (hours)
FORM IN CIRCULATION
Free (unbound)
Bound to blood
HALF LIFE IN BLOOD
Minutes
Hours
SITE OF ACTION ON THE
TARGET TISSUE
Specific receptor on
cell membrane
Specific receptor in
the cytoplasm or
nucleus
MECHANISM OF ACTION
Produce 2nd messenger
Activation of the
(transcription)
MOLECULAR BASIS OF
ACTION
Phosphorylation or
dephosphorylation of
enzyme
Synthesis of new
protein in cytoplasm
TRANSPORT AND SECRETION
MECHANISM
Vesicle-mediated
transport, released
by fusion of vesicle with
plasma membrane
nonvascular manner
by specific transporter
or diffusion
Mechanism of Hormone Transport in the Blood
1.
2.
3.
Bound (Steroids and Thyroid)
Free (Peptides)
Others
Mechanisms of Hormone Action
1-6
TABLE 4
MECHANISM OF HORMONE-RECEPTOR INTERACTION
A.
Peptide Hormones and Neurotransmitter Receptor Family
Type
1.
NH
Example
Seven transmembrane domain
β Adrenergic
PTH
GRH
LH
Glucagon
TSH
Dopamine
ACTH TRH
2
Plasma
Memb ran e
Cy tosol
CO H
2
2.
One or two transmembrane domains
Growth factor receptors
3.
a.
Group I - Receptor contains
intrinsic enzyme
i.e. tyrosine kinase
Insulin
IGF
EGF
b.
Group II - no intrinsic
tyrosine kinase
GH
Prolactin
Erythropoietin
Interleukin 2
Guanylyl Cyclase-linked receptors
Natriuretic peptides
B.
Steroid Receptor Family
Cytoplasmic receptor involving heat shock protein (HSP). When steroid hormone
binds to the receptor, HSP dissociates. This initiates transport of the receptor into
the nucleus.
C.
Thyroid Receptor Family
Includes thyroid receptor, retinoic acid receptor, vitamin D receptor. They are bound
to chromatin in the cell nucleus.
Mechanisms of Hormone Action
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Figure
Figure 32
MECHANISM OF SYNTHESIS OF PEPTIDE HORMONE
TATA
Ex on Intron
Exon
Intron
Exon
Gene-DNA
5'end
3'end
Start
Stop
Promoter
STRUCTURAL GENE
Transc ription
Pre-mRNA
Post trans cription
Mature m RNA
Translation
Pre-hormone (Prepeptide)
Post-trans lation
Hormone (peptide)
Mechanisms of Hormone Action
1-8
Figure 43
FIGURE
EXAMPLES OF NEGATIVE AND POSITIVE FEEDBACK IN
ENDOCRINOLOGY
STRESS
STIMULI
Negativ e
Hy pothalam us
C RH
Posterior
Pituitary
Positiv e
Oxy tocin
Negativ e
Anterior Pituitary
Cerv ic al
Rec eptor
Oxy tocin
ACTH
Positiv e Feedbac k
(terminates with deliv ery of f etus)
Adrenal Cortex
Cortis ol
Negativ e Feedback
Mechanisms of Hormone Action
1-9
Feedback Control (Figure 4)
Negative - Most common type of control. Signal stimulates release of hormone which in
turn feedbacks to the gland to reduce the signal and decrease hormone production.
(Example: adrenal, thyroid, parathyroid, pancreas)
Positive - Rare mechanism. Original signal for hormone production is further stimulated
by the signal to produce more hormone. Example: oxytocin release from PosteriorPituitary with labor pain. This activates cervical receptor to stimulate more oxytocin release
to accommodate expulsion of the fetus, but terminates with the delivery of the fetus.
Hormone Measurements and Assessment of Endocrine Function
Evaluation of endocrine function in clinical medicine requires, above all else, a thorough
history and physical examination of the patient which should form the basis of further
investigation and elucidation of pathogenesis. Without such a basic assessment, the
physician may subject the patient to unnecessary tests resulting in excess discomfort, pain,
and even harm, as well as financial burden.
Following is the list of methods for hormonal measurement:
Bioassay: A means of eliciting a specific physiologic response in an animal or living
biological preparation by a crude or purified hormone. This method usually is not sensitive
and requires large amounts of blood.
Chemical measurement: Determination of hormones by chemical method. It is more
sensitive than bioassay, but drugs may interfere with its measurement.
Radioimmunoassay (RIA): A specific antibody is harvested in an animal which will be
used in this test to bind the hormone in question. The amount of hormone in a biological
specimen (usually plasma) may then be quantitated by altering the extent of displacement
of trace amounts of the radioactively-labeled (e.g., 131I) hormone by the nonradioactive
hormone in a sample to be tested. This method is extremely sensitive and can detect
physiologic levels of hormones with as little as 0.05 ml of blood. However, the RIA method
does not distinguish between active or inactive hormones.
Enzyme-Linked ImmunoSorbent Assay (ELISA): ELISA, also called Enzyme
ImmunoAssay or EIA, is similar in hormone detection principle to RIA, except that a
nonradioactive (chemical) signal is used. In a typical ELISA test, an unknown amount of
antigen is affixed to a surface, and exposed to a specific antibody so that it can bind to the
antigen. The antibody is linked to an enzyme, and in the final step a substance (conjugate)
is added that the enzyme can convert to some detectable signal. For example, in
fluorescence ELISA, the antigen/antibody complex fluoresces upon exposure to light of
the appropriate wavelength.
Mechanisms of Hormone Action
1-10
Radioreceptor assay: This method is similar to RIA, but uses highly specific receptors on
cells or subcellular constituents rather than antibodies to measure biologically active
hormones. It is highly sensitive.
In certain cases all the above tests may be utilized. However, the most common and
frequently used method for hormone assay is RIA.
1.
Stimulation test: A hormone is used to elicit response from a target tissue, i.e.,
ACTH stimulation test to elicit glucocorticoid secretion from the adrenal glands.
2.
Suppression test: A physiologic or pharmacologic dose of a hormone is used to
assess feedback regulation of a hormone from the gland, i.e., in the dexamethasone
suppression test, the administration of potent exogenous glucocorticoiddexamethasone (which does not interfere with cortisol measurement) suppresses
endogenous production of the natural glucocorticoid (hydrocortisone-cortisol) from
the adrenal gland, under physiological conditions.
3.
Secretion rate: Amount of hormone secreted/unit time.
4.
Production rate: Hormone produced outside of the gland.
5.
Half life in blood: Time for hormone in the blood to fall to half of its original level or
concentration.
6.
Protein-bound fraction: The part of the hormone bound to a plasma-binding protein
(inactive hormone).
7.
Free or unbound fraction: The part of the hormone circulating free in the blood
(active hormone).
General Classification of Endocrine Disorders
Endocrine disorders may be classified under two general categories:
(1) Hyperfunction or (2) Hypofunction, each with the following subclassifications:
a.
Primary: increased (hyperfunction) or decreased (hypofunction) secretion
from the target gland (e.g., cortisol from adrenals).
b.
Secondary: increased or decreased secretion of trophic hormone (e.g.,
ACTH from pituitary) with resistant increase in target hormone (e.g. cortisol).
c.
Tertiary: increase or decrease of releasing hormone (e.g., CRH from
hypothalamus) with resistant increase in the trophic and thence the target
hormone.
Mechanisms of Hormone Action
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Hormone Receptor Interaction and Possible Mechanism of Hormone Resistant
States
As important as hormone hyper- and hyposecretion is in the pathogenesis of hormone
disorders, equally important is an abnormality of the hormone receptor which could be the
result of:
1.
decreased receptor number or affinity on the target tissue (decreased sensitivity);
2.
decreased receptor responsiveness (postreceptor defect);
3.
combination of 1 and 2 (decreased sensitivity and decreased responsiveness).
Mechanisms of Hormone Action
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120
____
% Maximal Response
__
100
Normal Response
____
__
80
Decreased
Sensitivity
____
__
60
Decreased
Responsiveness
____
__
40
____
Decreased
Sensitivity and
Responsiveness
__
20
____
__
0
0.01
0.1
1
10
100
Hormone Concentration (nM)
Figure 5: Types of resistance to hormone action. In hormone -resistant states
there may be a rightward shift of the dose -response curve (decreased
sensitivity), a decrease in maximal response (decreased re sponsiveness), or a
combination of the two. Decreased sensitivity indicates a defect at a non -ratelimiting step (often the receptor), whereas decreased responsiveness indicates a
defect at a rate-limiting step (usually post receptor). (Adapted from Kahn CR).
Insulin resistance, insulin insensitivity and insulin unresponsiveness: a
necessary distinction. Metabolism 1978; 27 [Suppl 2]: 1893 -1902.)
Mechanisms of Hormone Action
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