Transcript Document

Endocrine Physiology
Dale Buchanan Hales, PhD
Department of Physiology & Biophysics
Claude Bernard: the father of endocrinology
More than 100 years ago
Claude Bernard stated that the
endocrine system regulates the
internal milieu of an animal.
The “internal secretions” or
hormones were liberated by
one part of the body, traveled
via the bloodstream to distant
targets cells.
Endocrine system maintains
homeostasis
The concept that hormones acting on distant
target cells to maintain the stability of the
internal milieu was a major advance in
physiological understanding. The secretion
of the hormone was evoked by a change in
the milieu and the resulting action on the
target cell restored the milieu to normal.
The desired return to the status quo results
in the maintenance of homeostasis
Sensing and signaling
Endocrine “glands”
synthesize and store
hormones. These glands
have a sensing and
signaling system which
regulate the duration and
magnitude of hormone
release via feedback from
the target cell.
Endocrine vs. Nervous System
• Major communication systems in the body
• Integrate stimuli and responses to changes
in external and internal environment
• Both are crucial to coordinated functions of
highly differentiated cells, tissues and
organs
• Unlike the nervous system, the endocrine
system is anatomically discontinuous.
Principal functions of the
endocrine system
• Maintenance of the internal environment in the
body (maintaining the optimum biochemical
environment).
• Integration and regulation of growth and
development.
• Control, maintenance and instigation of sexual
reproduction, including gametogenesis, coitus,
fertilization, fetal growth and development and
nourishment of the newborn.
Hormones travel via the
bloodstream to target cells
Types of cell-to-cell signaling
Classic endocrine hormones
travel via bloodstream to
target cells; neurohormones
are released via synapses and
travel via the bloostream;
paracrine hormones act on
adjacent cells and autocrine
hormones are released and
act on the cell that secreted
them. Also, intracrine
hormones act within the cell
that produces them.
A cell is a target because is has a
specific receptor for the hormone
Major hormones and systems
• Top down organization of endocrine system.
• Hypothalamus produces releasing factors that
stimulate production of anterior pituitary hormone
which act on peripheral endocrine gland to
stimulate release of third hormone
– Specific examples to follow
• Posterior pituitary hormones are synthesized in
neuronal cell bodies in the hypothalamus and are
released via synapses in posterior pituitary.
– Oxytocin and antidiuretic hormone (ADH)
Classes of hormones
The hormones fall into two general classes
based on their solubility in water.
The water soluble hormones are the
catecholamines (epinephrine and
norepinephrine) and peptide/protein hormones.
The lipid soluble hormones include thyroid
hormone, steroid hormones and Vitamin D3
Water soluble hormones
 Water soluble hormones are synthesized in endocrine cells
and packaged into secretory granules.
 These granules fuse with the plasma membrane in an energy
dependent process called exocytosis and are released into the
extracellular fluid surrounding the cell.
 Water soluble hormones are freely soluble in the
bloodstream and can travel to their targets without being
bound to blood proteins– however, many are associated
with binding proteins that modulate their bioavailability
Lipid soluble hormones
 Lipid soluble hormones are synthesized in endocrine cells
but are not packaged in secretory granules.
 Lipid soluble hormones passively diffuse out of the
endocrine cell and become complexed with blood
proteins called globulins.
 The hormone protein complex is carried by the blood
stream to the target cells where the hormone is released
from the protein which enables it to bind to the target
cell receptor.
 Some lipid soluble proteins don’t have binding proteins,
for example, aldosterone.
Types of receptors
 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
Hormones and their receptors
Hormone
Class of
hormone
Location
Amine
(epinephrine)
Water-soluble
Cell surface
Amine (thyroid
hormone)
Lipid soluble
Intracellular
Peptide/protein
Water solube
Cell surface
Steroids and
Vitamin D
Lipid Soluble
Intracellular
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
Second messengers for cellsurface receptors
 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.
Second messenger systems
 Each of these second messenger systems activates
a specific protein kinase enzyme.
 These include cyclic nucleotide-dependent protein
kinases
 Calcium/calmodulin-dependent protein kinase, and
protein kinase C which depends on diacyl glycerol
binding for activation.
 Protein kinase C activity is further increased by calcium which
is released by the action of inositol phosphates.
Second messenger systems
 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
Cell surface receptor action
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.
Receptors for lipid-soluble
hormones reside within the cell
 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
Types of hormones-1
Amine hormones:
Hormones derived from the amino acid
tyrosine.
These include epinephrine, norepinephrine
and thyroid hormone.
Epinephrine and norepinephrine are produced
by the adrenal medulla –water soluble
Thyroid hormone is produced by the thyroid
gland –lipid soluble
Types of hormones -2
Peptide/protein hormones:
Range from 3 amino acids to hundreds of
amino acids in size.
Often produced as larger molecular weight
precursors that are proteolytically cleaved to the
active form of the hormone.
Peptide/protein hormones are water soluble.
Comprise the largest number of hormones–
perhaps in thousands
Types of hormones-3
Steroid hormones:
All steroid hormones are derived from
cholesterol and differ only in the ring structure
and side chains attached to it.
All steroid hormones are lipid soluble
1,25-dihydroxy Vitamin D3 is also derived
from cholesterol and is lipid soluble
Peptide/protein hormones
• Are encoded by a specific gene which is transcribed into
mRNA and translated into a protein precursor called a
preprohormone
• Preprohormones are often post-translationally modified in
the ER to contain carbohydrates (glycosylation)
• Preprohormones contain signal peptides (hydrophobic
amino acids) which targets them to the golgi where signal
sequence is removed to form prohormone
• Prohormone is processed into active hormone and
packaged into secretory vessicles
Peptide/protein hormones
• Secretory vessicles move to plasma membrane where they
await a signal. Then they are exocytosed and secreted into
blood stream
• In some cases the prohormone is secreted and coverted in
the extracellular fluid into the active hormone: an example
is angiotensin is secreted by liver and converted into active
form by enzymes secreted by kidney and lung
Peptide/protein hormone synthesis
Steroid hormones
• Are not packaged, but synthesized and immediately
released
• Are all derived from the same parent compound:
Cholesterol
• Enzymes which produce steroid hormones from
cholesterol are located in mitochondria and smooth ER
• Steroids are lipid soluble and thus are freely permeable to
membranes so are not stored in cells
Steroid hormones
• Steroid hormones are not water soluble so have to be
carried in the blood complexed to specific binding
globulins.
• Corticosteroid binding globulin carries cortisol
• sex steroid binding globulin carries testosterone and
estradiol
• In some cases a steroid is secreted by one cell and is
converted to the active steroid by the target cell: an
example is androgen which secreted by the gonad and
converted into estrogen in the brain
Steroid hormone synthesis
All steroid hormones are
derived from cholesterol. A
series of enzymatic steps in the
mitochondria and ER of
steroidogenic tissues convert
cholesterol into all of the other
steroid hormones and
intermediates. 1,25-dihydroxy
Vitamin D3 is also derived
from cholesterol
Steroids can be transformed to
active steroid in target cell
Amine hormones:
derived from tyrosine
• Epinephrine, norepinephrine and dopamine are water
soluble and are synthesized and secreted like peptide
hormones
• Thyroid hormones are produced by modification of a
tyrosine residue contained in thyroglobulin, posttranslationally modified to bind iodine, then proteolytically
cleaved and released as T4 and T3. T3 and T4 then bind to
thyroxin binding globulin for transport in the blood
Synthesis of catecholamines
Thyroid hormones
Regulation of hormone secretion
 Sensing and signaling: a biological need is sensed,
the endocrine system sends out a signal to a target
cell whose action addresses the biological need.
Key features of this stimulus response system are:





receipt of stimulus
synthesis and secretion of hormone
delivery of hormone to target cell
evoking target cell response
degradation of hormone
Feedback control
• Negative feedback is most common: for example,
LH from pituitary stimulates the testis to produce
testosterone which in turn feeds back and inhibits
LH secretion
• Positive feedback is less common: examples
include LH stimulation of estrogen which
stimulates LH surge at ovulation
Control of hormonal secretion
• Humoral
• Neural
• Hormonal
Regulation of hormone release
1. hormone-hormone
2. substrate-hormone
3. mineral-hormone
Substrate-hormone control
• glucose and insulin: as glucose increases it
stimulates the pancreas to secrete insulin
Neural control
• Neural input to hypothalamus stimulates
synthesis and secretion of releasing factors
which stimulate pituitary hormone
production and release
Inputs to endocrine cells
Chronotropic control
• Endogenous neuronal rhythmicity
• Diurnal rhythms, circadian rhythms (growth
hormone and cortisol), Sleep-wake cycle;
seasonal rhythm
Circadian (chronotropic) control
Circadian Clock
Negative feedback effects of cortisol
Feedback control of insulin by
glucose concentrations
Hormonal interactions
• Permissive
• Synergistic
• Antagonistic
Spare receptors
• The "spare receptor" concept is based on this relationship
and is states that maximum biological activity is often
obtained when only 5 to 10% of the receptors are bound.
• When the number of spare receptors are decreased
maximum biological activity is achieved at a higher
concentration of hormone. Therefore, the greater the
number of receptors, the greater the sensitivity of them to
hormone
Hypothalamus
• main releasing controler of pituitary
secretions
• production of hormones of posterior pituitary
• many other control centers here - ANS,
hunger, thirst, temperature, biological clock
• General name releasing or inhibiting hormone
or factor
Hypothalamus
• Thyrotropin
releasing hormone
TRH
Gonadotropin
“
“
GnRH
Corticotropin
“
“
CRH
Growth hormone
“
“
GHRH
Growth hormone inhibiting hormone
GHIH (somatostatin)
• Prolactin inhibiting hormone
PIH = dopamine
Prolacting - releasing hormone
PRH
Hypothalamus
• Growth hormone inhibiting hormone GHIH
(somatostatin)
• Prolactin inhibiting hormone
PIH = dopamine
• Prolacting - releasing hormone
PRH
Anterior pituitary
• Control of other endocrine gland secretions
and direct effects
• Direct effects:
• Somatotropin or Growth hormone
ST or GH
– controls metabolism and growth
• Prolactin
PRL
– milk secretion
Anterior pituitary
Control of endocrine glands:
• Thyroid stimulating hormone
TSH
– Secretion of thyroid hormone
• Adrenocorticotropic hormone
– Secretion of glucocorticoids, androgens and
mineralocorticoids to a lesser extent
ACTH
Anterior pituitary
Control of endocrine glands:
• Follicle stimulating hormone
FSH
– follicle growth, estrogen secretion
– stimulates sperm production
• Lutenizing hormone
LH
– triggers ovulation and estrogen and progesterone
production
– promotes testosterone production
Posterior Pituitary
Storage and release of hypothalamic hormones
• Oxytocin
OT
– Uterine contractions and milk ejection
• Antidiuretic hormone
ADH
– production of concentrated low volume urine
Pineal
• Circadian rhythms
• Serotonin, norepinephrine, dopamine,
histamine MAIN melatonin
Thyroid
• Metabolic rate and Ca++ and PO4-3 balance
• Role in growth and development
– thyroid
– calcitonin
Parathyroid
• Ca++ and PO4-3 balance
– parathyroid hormone
Thymus
• Immune function
– thymic hormones
Adrenals
• Stress response
– cortex - mineralocorticoids, glucocorticoids and
gonadocorticoids
– medulla - which is of course part of the
sympathetic NS but acts in an endocrine
function to prolong the sympathetic response
Pancreas
• Glucose metabolism energy accessibility
–
–
–
–
insulin (beta cells)
glucagon (alpha cells)
somatostatin or GHIH (delta cells)
amylin (beta cells) -
Gonads
• Reproductive function
– Female estrogens and progesterone
– Males testosterone
Other organs which produce
hormones
• GI tract
Stomach - gastrin and serotonin
– in stomach release of HCl and contraction
Duodenum - secretin and cholecyctokinin
– in pancreas release of bicarbonate and enzymes
• Kidney- erythropoetin
– production of RBCs in bone marrow
Other organs which produce
hormones
• Skin- cholecalciferol
– from vitamin D activated in the kidneys to
calcitirol promotes Ca++ absorption
• Heart - atrial natriuretic factor ( ANF)
– in kidneys inhibits Na+ reabsoption and renin
release and inhibits secretion of aldosterone by the
adrenal cortex
• Placenta- a bunch of hormones including progesterone and
estrogen , human chorionic gonadotropin and others