ENDOCRINE SYSTEM Endocrine system Composed of glands

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ENDOCRINE SYSTEM
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ENDOCRINE SYSTEM

• Endocrine system
• Composed of glands
• Ductless glands
• Secrete chemical signals into the bloodstream
• (Exocrine glands secrete substances through
  ducts to surfaces)
• Secretory products are hormones

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HORMONES

• Hormones
• Chemical signal (ligand)
• Produced in minute amounts by a collection of
  cells
• Secreted into the interstitial spaces
• Enters the circulatory system
• Transported throughout the body
• Influences the activity of specific tissues
• Target tissues

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REGULATION

• Endocrine and nervous systems both regulate the
  activities of structures within the body
• Accomplished in different ways
• Hormones are amplitude-modulated signals
• Signals consist mainly of increases or decreases
  in the concentration of hormones in body fluids
• Response produced within several seconds to hours
• Action potentials are frequency-modulated signals
• Action potentials vary in frequency but not in
  amplitude
• Response produced within milliseconds

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REGULATION

• Nervous and endocrine systems are intimately
  related
• The two systems cannot be completely separated
  either anatomically or functionally
• e.g., Some neurons secrete neurohormones into the
  circulatory system
• Function like hormones
• e.g., Some neurons directly innervate endocrine
  glands and influence their secretory activity
• e.g., Some hormones secreted by endocrine glands
  affect the nervous system and influence its
  activity

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CHEMICAL SIGNALS

• Intercellular chemical signals allow cells to
  communicate with each other
• e.g., Neurotransmitters, neuromodulators, and
  hormones
• There are various types of intercellular signals
• Autocrine chemical signals
• Paracrine chemical signals
• Pheromones

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CHEMICAL SIGNALS

• Autocrine chemical signals
• Released by cells and have an effect on similar
  cells
• e.g., Prostaglandins are released by smooth
  muscle cells and platelets in response to
  inflammation
• Causes aggregation of platelets and relaxation of
  blood vessel smooth muscle

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CHEMICAL SIGNALS

• Paracrine chemical signals
• Released by cells and affect other cell types
  locally without being transported in the blood
• e.g., The peptide somatostatin is released by
  cells in the pancreas and functions locally to
  inhibit the secretion of insulin from other cells
  of the pancreas

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CHEMICAL SIGNALS

• Pheromones
• Secreted into the environment and modify the
  behavior and physiology of other individuals
• e.g., Pheromones released in urine of cats and
  dogs signal fertility
• e.g., Pheromones released by women influence the
  menstrual cycles of other women

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CHEMICAL SIGNALS

• Many intercellular chemical signals consistently
• Intercellular signals
• Many consistently fit one specific definition
• Many do not consistently fit one specific
  definition
• e.g., Norepinephrine functions both as a
  neurotransmitter and a neurohormone

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HORMONE STRUCTURE

• Three main classes of hormones
• Polymers of amino acids
• Proteins or polypeptides
• Glycoprotein hormones contain carbohydrate
  components
• Derivatives of single amino acids
• Lipids
• Steroids or derivatives of fatty acids

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SECRETION

• Most hormones are not secreted at a constant rate
• Secretion increases and decreases dramatically
  over time
• Secretion rate generally controlled by negative
  feedback
• Body activity regulated is maintained within
  normal range
• Homeostasis is maintained
• Secretion is sometimes regulated by positive
  feedback
• Less frequent
• e.g., components of the female reproductive
  system
• Estrogen stimulates LH secretion
• LH stimulates estrogen secretion

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SECRETION

• Three major patterns of regulation
• Changes in the extracellular concentration of a
  non-hormone molecule can affect an endocrine
  gland
• Neural control of the endocrine gland
• Control of hormone secretion by another hormone
  or neurohormone
• Regulation of hormone secretion often involves
  more than one of these mechanisms

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SECRETION

• Changes in the extracellular concentration of a
  non-hormone molecule can affect an endocrine
  gland
• e.g., Blood glucose levels affect insulin
  secretion from the pancreas
• Insulin increases glucose movement into cells
• Insulin secretion decreases

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SECRETION

• Neural control of the endocrine gland
• Neurons synapse with hormone-producing cells
• Neurotransmitter release stimulates or inhibits
  hormone release
• e.g., Stress or exercise stimulates the adrenal
  gland to secrete epinephrine and norepinephrine

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SECRETION

• Control of hormone secretion by another hormone
  or neurohormone
• e.g., Thyroid-releasing hormone (TRH) from the
  hypothalamus stimulates the secretion of
  thyroid-stimulating hormone (TSH) from the
  anterior pituitary gland
• TSH stimulates the secretion of thyroid hormones
  (T3 T4)
• etc.

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SECRETION

• Some hormones are in the circulatory system at
  relatively constant levels
• e.g., Thyroid hormones
• Levels of some hormones change suddenly in
  response to certain stimuli
• e.g., Epinephrine is released in response to
  stress or exercise
• Levels of some hormones change in relatively
  constant cycles
• e.g., Reproductive hormones cycle in women during
  their reproductive years

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SECRETION

• Some hormones are in the circulatory system at
  relatively constant levels
• e.g., Thyroid hormones

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SECRETION

• Levels of some hormones change suddenly in
  response to certain stimuli
• e.g., Epinephrine is released in response to
  stress or exercise

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SECRETION

• Levels of some hormones change in relatively
  constant cycles
• e.g., Reproductive hormones cycle in women
  during their reproductive years

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HORMONE TRANSPORT

• Hormones are dissolved in blood plasma
• Transported in two fashions
• Free form
• Bound to plasma proteins

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HORMONE TRANSPORT

• Free hormones diffuse readily into interstitial
  spaces
• Concentration of hormone in the blood affects the
  amount of hormone diffusing into interstitial
  spaces

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HORMONE TRANSPORT

• Many hormones bind only to certain types of
  plasma proteins
• e.g., The type of plasma protein binding to
  thyroid hormones differs from the type of plasma
  protein binding to testosterone

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HORMONE TRANSPORT

• Hormones that bind to plasma proteins do so
  reversibly
• H BP ? HBP
• This equilibrium is important
• Only free hormone can diffuse into the
  interstitial space
• Hormones bound to plasma proteins tend to remain
  at a relatively constant level in the blood for
  long periods of time
• Decrease in plasma protein concentration reduces
  half-life of hormone

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HORMONE TRANSPORT

• A decrease in plasma protein concentration
  reduces the half-life of hormone
• Eliminated in either the kidneys of the liver

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HORMONE TRANSPORT

• The circulatory system quickly distributes
  hormones throughout the body
• Diffuse through capillary endothelium
• Rate varies between hormones
• Lipid-soluble hormones readily diffuse through
  the walls of all capillaries
• Water-soluble hormones pass through pores
  (fenestrae) in the capillary endothelium
• Capillary endothelia of organs regulated by
  protein hormones have large pores
• Endocrine glands secreting these hormones also
  have large pores

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METABOLISM EXCRETION

• Hormone destruction and elimination limit the
  time in which they are active
• Water-soluble hormones have relatively short
  half-lives
• Rapidly degraded by enzymes
• Present in circulatory system or organs
• Normally have concentrations that increase and
  decrease rapidly
• Generally regulate activities that have a rapid
  onset and a short duration

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METABOLISM EXCRETION

• Hormone destruction and elimination limit the
  time in which they are active
• Lipid-soluble hormones have relatively long
  half-lives
• Commonly circulate in the blood bound to plasma
  proteins
• Reduces rate of elimination
• Reduces rate at which they diffuse through
  capillary endothelium
• Normally maintained at relatively constant levels

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METABOLISM EXCRETION

• Four main modes of hormone removal from the blood
• Excretion
• Metabolism
• Active transport
• Conjugation

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METABOLISM EXCRETION

• Four main modes of hormone removal from the blood
• Excretion
• Kidneys excrete hormones into the urine
• Liver excretes hormones into the bile

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METABOLISM EXCRETION

• Four main modes of hormone removal from the blood
• Metabolism
• Hormones metabolized or chemically modified
• Enzymes in blood or tissues
• e.g., Liver, kidneys, lungs, etc.
• End products may be excreted in urine or bile
• End products may be taken up by cells
• e.g., Epinephrine is modified, then excreted
• e.g., Protein hormones are broken down into amino
  acids
• Amino acids are then taken up by cells

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METABOLISM EXCRETION

• Four main modes of hormone removal from the blood
• Active transport
• Actively transported into cells
• Hormones are recycled
• e.g., Epinephrine and norepinephrine are actively
  transported into cells
• These hormones can be secreted again

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METABOLISM EXCRETION

• Four main modes of hormone removal from the blood
• Conjugation
• Attachment of water-soluble molecules to hormones
• Typically sulfate or glucuronic acid
• Increases rate of excretion by kidneys or liver

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INTERACTION WITH TARGET TISSUES

• Intercellular chemical signals
• Ligands
• Bind to proteins and change their functions
• Various classes
• Hormones
• Neurotransmitters
• Chemical mediators of inflammation

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INTERACTION WITH TARGET TISSUES

• Ligands bind to proteins at their binding site
• Receptor site if protein is a receptor
• Lock-and-key fit
• Specificity
• e.g., Insulin binds to insulin receptors
• e.g., Insulin does not bind to growth hormone
  receptors
• Multiple types of receptors exist for some
  hormones
• e.g., There are multiple types of epinephrine
  receptors

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INTERACTION WITH TARGET TISSUES

• Hormones are distributed throughout the body by
  the circulatory system
• Target cells respond to a given hormone
• Possess receptors to which the hormone binds
• Cells lacking receptors do not respond

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INTERACTION WITH TARGET TISSUES

• Drugs with structures similar to a particular
  chemical signal may compete with that molecule
  for their receptor sites
• Binding some drugs activates the receptors
• Binding of some drugs inhibits the receptor
• Blocks binding by the hormone
• e.g., RU486 binds to progesterone receptors
• Prevents binding by progesterone
• Prevents the maintenance of pregnancy

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INTERACTION WITH TARGET TISSUES

• Response to a given concentration of chemical
  signal
• Constant in some cases
• Variable in some cases
• Two common reasons
• Fatigue in the target cells after prolonged
  stimulation
• Number of receptors can decrease after exposure
  to certain chemical signals
• Down-regulation
• Two mechanisms
• Decreased rate of receptor synthesis
• Increased rate of receptor degradation

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INTERACTION WITH TARGET TISSUES

• Neurons of the hypothalamus release GnRH
• Causes secretion of FSH and LH from the anterior
  pituitary
• Exposure to GnRH causes a reduction in the number
  of GnRH receptors in cells of the anterior
  pituitary
• Dramatic decrease several hours after exposure
• Pituitary becomes less sensitive to GnRH
• Normal response of pituitary depends on periodic
  (not constant) exposure to GnRH

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INTERACTION WITH TARGET TISSUES

• Tissues exhibiting down-regulation of receptors
  generally respond to short-term increases in
  hormone concentrations
• Tissues responding to relatively constant levels
  of hormones normally do not exhibit
  down-regulation

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INTERACTION WITH TARGET TISSUES

• Periodic increases in sensitivity to certain
  hormones can also occur
• Up-regulation
• Results from an increase in the rate of receptor
  molecule synthesis
• e.g., Increased number of LH receptors in the
  ovary during each menstrual cycle
• FSH from pituitary increases synthesis of LH
  receptor

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CLASSES OF RECEPTORS

• Two main categories of chemical signals
• (And two main categories of receptors)
• Those binding to membrane-bound receptors
• Those binding to intracellular receptors

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CLASSES OF RECEPTORS

• Some chemical signals cannot pass through the
  plasma membrane
• Large molecules and water-soluble molecules
• Bind to membrane-bound receptors
• Transmembrane receptor proteins
• Receptor site exposed on outer surface
• Binding of signal to receptor initiates a
  response inside the cell

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CLASSES OF RECEPTORS

• Some chemical signals readily pass through the
  plasma membrane
• Small and lipid soluble molecules
• Bind to intracellular receptors
• Hormone-receptor complex may bind to DNA
• Alters gene expression
• Hormone-receptor complex may bind to enzymes

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CLASSES OF RECEPTORS

• Signals binding to membrane-bound receptors
• Protein hormones
• Glycoprotein hormones
• Polypeptides
• Some smaller molecules
• Epinephrine
• Norepinephrine
• etc.

• Signals binding to intracellular receptors
• Thyroid hormones
• Steroid hormones
• Testosterone
• Estrogen
• Progesterone
• Aldosterone
• Cortisol
• etc.

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CLASSES OF RECEPTORS

• Membrane-bound receptors
• Integral membrane proteins
• Hormone-receptor binding is reversible
• Binding stimulates the intracellular portion of
  receptor to initiate a response
• Three major mechanisms of responses
• Altered membrane permeability
• Altered activity of G proteins
• Altered activity of intracellular enzymes

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CLASSES OF RECEPTORS

• Receptors altering membrane permeability
• Some receptors comprise part of an ion channel
• Ligand-gated ion channels
• Binding alters shape of channel
• Causes channel to either open or close
• Results in a change in the membranes
  permeability to the specific ions passing
  through the channel

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• G proteins
• Bind to receptors at inner surface of plasma
  membrane
• Inactive state binds to GDP

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• Receptor changes shape upon binding to hormone
• GTP replaces GDP on G protein
• Alpha subunit separates from other subunits
• Alpha subunit can influence ion channels or form
  intracellular mediators (second messengers)

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• Hormone separates from the receptor
• G proteins are no longer activated
• Alpha subunits are inactivated as GTP ? GDP

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• Some G proteins activate Ca2 channels
• Ca2 enters the cell
• Can function as an intracellular mediator
• Enters or is synthesized inside the cell
• Regulates enzyme activities inside the cell

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• Ca2 can combine with calmodulin molecules
• Calcium-calmodulin complexes activate enzymes
• Thee enzymes cause contraction of smooth muscle

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CLASSES OF RECEPTORS

• Receptors activating G proteins
• Some G proteins alter enzyme activity
• Activated alpha subunits can activate the enzyme
  adenylate cyclase
• ATP ? cAMP
• cAMP binds to kinases
• Activated kinases phosphorylate other enzymes
• Activity of these enzymes is altered
• Either increased or decreased
• cAMP is inactivated (cAMP? AMP) by the enzyme
  phosphodiesterase

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CLASSES OF RECEPTORS

• Cyclic AMP acts as an intracellular mediator in
  many cell types
• Enzymes activated are different
• Response of each cell type is different
• e.g., Glucagon ? release of glucose from liver
  cells
• e.g., LH ? ovulation

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CLASSES OF RECEPTORS

• The combination of chemical signals with their
  receptors doesnt always result in increased cAMP
  synthesis
• Sometimes cAMP synthesis is inhibited by G
  proteins
• There are other common intracellular mediators
• e.g., Diacyl glycerol (DAG)
• e.g., Inositol triphosphate (IP3)

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CLASSES OF RECEPTORS

• Epinephrine binds to certain receptors in some
  types of smooth muscle
• Binding activates a G protein
• Phospholipase C is activated
• Phosphoinositol diphosphate (PIP2) ? DAG IP3
• DAG activates enzymes that synthesize
  prostaglandins
• Smooth muscle contraction is increased
• IP3 releases Ca2 from the E.R.
• Ca2 enters the cytoplasm and increases smooth
  muscle contraction

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Intracellular enzymes controlled by the
  membrane-bound receptors
• May be part of the receptor
• May be separate molecules

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Effects of altered enzyme activity
• Increased or decreased synthesis of intracellular
  mediator molecules
• Phosphorylation of intracellular proteins
• Effects of intracellular mediators or
  phosphorylated proteins
• Activation of processes that produce the response
  of cells to the chemical signals

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Intracellular mediator molecules act as chemical
  signals
• Move from enzymes that produced them into the
  cytoplasm
• Activate processes that produce the response of
  the cell

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Cyclic guanine monophosphate
• cGMP
• Intracellular mediator molecule
• Synthesized in response to chemical signal
  binding with a membrane-bound receptor
• Produced by the enzyme guanylate cyclase
• GTP ? cGMP

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Cyclic guanine monophosphate
• Combine with and activate specific cytoplasmic
  enzymes
• Activated enzymes produce the response of the
  cell to the chemical signal

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• e.g., ANH binds to receptor in kidney cell
  membrane
• Increased cGMP synthesis
• Influences action of enzymes
• Stimulates Na and H2O excretion
• Phosphodiesterase breaks down cGMP
• cGMP ? GMP
• Signal quickly disappears when hormone disappears

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CLASSES OF RECEPTORS

• Some receptors directly alter the activity of
  intracellular enzymes
• Cytoplasmic portion of receptor acts as a
  phosphorylase enzyme
• Phosphorylates several specific proteins
• Some are part of the membrane-bound receptor
• Others are cytoplasmic
• proteins
• Phosphorylated proteins influence activity of
  other cytoplasmic enzymes

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CLASSES OF RECEPTORS

• Many hormones stimulate the synthesis of an
  intracellular mediator molecule
• Often produce rapid responses
• Mediator influences already-existing enzymes
• Causes a cascade event
• Few mediator molecules activate several enzymes
• Each activated enzyme activates several other
  enzymes
• Final response is produced

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CLASSES OF RECEPTORS

• Intracellular receptors
• Present in either the cells cytoplasm or nucleus
• Lipid-soluble chemical signals
• Cross the plasma membrane
• Bind to intracellular receptors
• Hormone-receptor complex has one of two effects
• Alter the activity of cellular enzymes
• Bind to DNA and alter the expression of genes

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CLASSES OF RECEPTORS

• Receptors binding to DNA
• Activate certain specific genes
• Transcription of these genes increases
• Specific proteins are produced
• e.g., Testosterone and estrogen stimulate the
  production of the proteins responsible for
  secondary sexual characteristics
• e.g., Aldosterone stimulates kidney cells to
  synthesize proteins increasing the rate of Na
  and K transport
• Results in increased reabsorption of Na and
  increased K secretion

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CLASSES OF RECEPTORS
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CLASSES OF RECEPTORS

• Cells synthesizing proteins in response to
  hormonal stimuli normally have a latent period of
  several hours
• Hormones bind, responses are observed