Introduction to Introduction to EndocrinologyEndocrinology
Physiology of the endocrine system by
Dr Ehsan Saboory
Professor of physiology
Department of physiology, Faculty of medicine, Urmia University of Medical Sciences
Endocrine System: OverviewEndocrine System: Overview
• Endocrine system – the body’s second great controlling system which influences metabolic activities of cells by means of hormones
• Endocrine glands – pituitary, thyroid, parathyroid, adrenal, pineal, and thymus glands
• The pancreas and gonads produce both hormones and exocrine products
• The hypothalamus has both neural functions and releases hormones
• Other tissues and organs that produce hormones – adipose cells, pockets of cells in the walls of the small intestine, stomach, kidneys, and heart
HormonesHormones
• Hormones – chemical substances secreted by cells into the extracellular fluids
• Regulate the metabolic function of other cells
• Have lag times ranging from seconds to hours
• Tend to have prolonged effects
• Are classified as amino acid-based hormones, or steroids
• Eicosanoids – biologically active lipids with local hormone–like activity
Types of HormonesTypes of Hormones
• Amino acid–based – most hormones belong to this class, including:
• Amines, thyroxine, peptide, and protein hormones
• Steroids – gonadal and adrenocortical hormones
• Eicosanoids – leukotrienes and prostaglandins
Hormone ActionHormone Action
• Hormones alter cell activity by one of the following mechanisms:
• Direct changes in cell membrane permeability
• Second messengers involving:
• Regulatory G proteins (amino acid–based hormones)
• Direct gene activation involving steroid hormones
• The precise response depends on the type of the target cell and its receptor
Mechanism of Hormone ActionMechanism of Hormone Action
• Hormones produce one or more of the following cellular changes:
• Alter plasma membrane permeability
• Stimulate protein synthesis
• Activate or deactivate enzyme systems
• Induce secretory activity
• Stimulate mitosis
• Hormone (first messenger) binds to its receptor, which then binds to a G protein
• The G protein is then activated as it binds GTP, displacing GDP
• Activated G protein activates the effector enzyme adenylate cyclase
• Adenylate cyclase generates cyclic AMP (cAMP) (second messenger ) from ATP
• cAMP activates protein kinases, which then cause cellular effects
Amino Acid–Based Hormone Action: cAMPAmino Acid–Based Hormone Action: cAMP
An Increase in cAMP Leads to:An Increase in cAMP Leads to:
Activation of PKA which may cause :
• Activation or deactivation of numerous enzymes
• CREB→CREB-P + transcription factor 1→add to CRE
• Stimulation or inhibition of RNA polymerase
• Transcription of genes
• cAMP finally hydrolyzed by phosphodiestrase (PD)
• Activity of PD is also modulated by hormones via a G protein( dual regulation)
• Two hormones can function antagonistically of one stimulates AC and the other stimulates PD
Figure 15.1a
Amino Acid–Based Hormone Action: Amino Acid–Based Hormone Action: cAMP Second MessengercAMP Second Messenger
• H binds to the receptor and activates G protein
• G protein binds and activates a PLC enzyme
• PLC splits the PIP2 into DAG and IP3 (both act as second messengers)
• DAG activates protein kinase C; IP3 triggers release of Ca2+ stores (PKC is Ca2+ dependent)
• Ca2+ (third messenger) alters cellular responses
• Arachidonic acid is derived from hydrolysis of DAG serve as a substrate of prostaglandins (PG)
• The PGs are also modulators of hormonal response
Amino Acid–Based Hormone Action: Amino Acid–Based Hormone Action: PIP–CalciumPIP–Calcium
Figure 15.1b
Amino Acid–Based Hormone Action: Amino Acid–Based Hormone Action: PIP–CalciumPIP–Calcium
Other types of Other types of Signal transductionSignal transduction ( (STST))
• 2 other mechanisms of ST from surface R are known in which the transducers lie in the cytoplasmic tail of the R
• In one of these, H+R→ autophosphorylation of R→ the R itself becomes a tyrosine kinase and P the tyrosine residues on intracellular protein. Tyrosine P initiates a cascade of serine and threonine P of enzymes
• Causes multiple intracellular events (Metabolism, proliferation and differentiation), e.g. Insulin
• In the second one H+R→ conformational changes in R which attracts and docks tyrosine kinases e.g. GH
• Another second messenger is cGMP→ activates PKG
Steroid HormonesSteroid Hormones
• Steroid hormones and thyroid hormone diffuse easily into their target cells
• Once inside, they bind and activate a specific intracellular receptor
• The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor
• This interaction prompts DNA transcription to produce mRNA
• The mRNA is translated into proteins, which bring about a cellular effect
Intracellular receptors (Intracellular receptors (steroidsteroid))• These R are large oligomeric and usually phosphorylated
• Related to cis-oncogens family and contain 3 domains :
• Variable C-terminus binds the H and is unique to each R
• middle domain contains a DNA site formed by 2 fingers
• N-terminus domain is variable in length( transactivating)
• Unoccupied R is inactive or blocked by a molecule
• H binding displaces the blocking molecule and translocates into the nucleus, undergo dimerization, binds to a specific site on DNA (HRE) → activates the RNA polymerase
• Negative regulatory elements also exist in DNA molecules
• These are characteristic of adrenal steroid hormones
Intracellular receptors (Intracellular receptors (thyroxinthyroxin))
• In another general model of activation which is characteristic of thyroid hormones and Vit D the unoccupied R is already attached to DNA binding sites and prevents gene transcription
• H binds R and relieves the suppressive effect of the R
• In a variant of this model, H binding causes dissociation of the two identical receptor monomers constituting the homodimer, formation of heterodimer which activates the gene transcription
Hormone–Target Cell SpecificityHormone–Target Cell Specificity
• Hormones circulate to all tissues but only activate cells referred to as target cells
• Target cells must have specific receptors to which the hormone binds
• These receptors may be intracellular or located on the plasma membrane
• Examples of hormone activity
• ACTH receptors are only found on certain cells of the adrenal cortex
• Thyroxin receptors are found on nearly all cells of the body
Target Cell ActivationTarget Cell Activation
• Target cell activation depends upon three factors
• Blood levels of the hormone
• Relative number of receptors on the target cell
• The affinity of those receptors for the hormone
• Up-regulation – target cells form more receptors in response to the hormone
• Down-regulation – target cells lose receptors in response to the hormone
Receptor KineticsReceptor Kinetics
• H+R =HR , K= HR/[H][R] , [HR]/[H]= K × [R]
• H= free hormone in solution R=unoccupied receptor HR=bound hormone =occupied receptor R0= initial receptor capacity = [R] + [HR] K = affinity constant
Schatchard plot for HR kineticSchatchard plot for HR kinetic
A linear plot results when the H reacts with a single R class and no cooperativity is present. The negative of the K equals the slope of the line. The R number,R0, equals the intercept with the X axis.
Schatchard plot for HR kineticSchatchard plot for HR kinetic An exponential
plot results when the H occupancy of one R molecule alters the local affinity of a second nearby molecule for the H. This phenomenon called negative cooperativity.
A, The general shape of a H dose-response curve. Sensitivity is expressed as the concentration of the H that produces half-max response.
B, Alterations in dose-response curve results from changes in max responsiveness, sensitivity, or both.
Hormone Concentrations in the BloodHormone Concentrations in the Blood
• Concentrations of circulating hormone reflect:
• Rate of release
• Speed of inactivation and removal from the body
• Hormones are removed from the blood by:
• Degrading enzymes
• The kidneys
• Liver enzyme systems
Control of Hormonal SecretionControl of Hormonal Secretion
• Feedback control• Positive feedback:
• Stimulus detected, H released, H reaches target cell, H binds R, Effect produced, Feedback to endocrine structure, More H released
• Negative feedback:• Stimulus detected, H released, reaches target cell, binds R,
Effect produced, Feedback to endocrine structure, Hormone release shut down
• Direct nerve control• Autonomic nervous system
• Inhibiting hormones or Releasing hormones
• Chronotropic control
Control of Hormone Synthesis and ReleaseControl of Hormone Synthesis and Release
• Blood levels of hormones:
• Are controlled by negative feedback systems
• by positive feedback systems (seldom)
• Vary only within a narrow desirable range
• Hormones are synthesized and released in response to:
• Humoral stimuli (substrate or mineral- hormone)
• Neural stimuli
• Hormonal stimuli (hormone- hormone)
Humoral StimuliHumoral Stimuli
• Humoral stimuli – secretion of hormones in direct response to changing blood levels of ions and nutrients
• Example: Declining blood Ca2+ concentration stimulates the parathyroid glands to secrete PTH (parathyroid hormone)
• PTH causes Ca2+ concentrations to rise and the stimulus is removed Figure 17.3a
Neural StimuliNeural Stimuli
• Neural stimuli – nerve fibers stimulate hormone release
• Preganglionic sympathetic nervous system (SNS) fibers stimulate the adrenal medulla to secrete catecholamines
Figure 15.3b
Hormonal StimuliHormonal Stimuli
• Hormonal stimuli – release of hormones in response to hormones produced by other endocrine organs
• The hypothalamic hormones stimulate the anterior pituitary
• In turn, pituitary hormones stimulate targets to secrete still more hormones
Figure 15.3c
Nervous System ModulationNervous System Modulation
• The nervous system modifies the stimulation of endocrine glands and their negative feedback mechanisms
• The nervous system can override normal endocrine controls
For example, control of blood glucose levels
• Normally the endocrine system maintains blood glucose
• Under stress, the body needs more glucose
• The hypothalamus and the sympathetic nervous system are activated to supply ample glucose
Chronal control (the circadian rhythms=CR)Chronal control (the circadian rhythms=CR)
The origin of CR in H secretion, behavioral and metabolic activity.
A clock with a 24-25h cycle is located in the SCN, this free running clock is entrained by environmental light signals to the external 24h day.
It has bidirectional relationship with the sleep-wake cycle,too.
Type of cell to cell signalingType of cell to cell signaling
• Endocrine: hormone enters the blood stream
• Neurocrine (neuroendocrine): also enters the blood
• Paracrine:through Int. fluid or GJ to another cell type
• Autocrine: through Int. fluid or gap junction and act on neighboring identical cells or back to the cell of origin
• Juxtacrine ?
Types of hormone synthesis Types of hormone synthesis
• Protein or peptide hormone synthesis
• Aminoacid based hormone synthesis
• Steroid hormone synthesis
• Eicosanoids synthesis
Hormone release Hormone release • Release of protein and catecholamine hormones
• Release of Thyroid and steroid hormones
• Other forms of hormone release
• Two adjacent cell types in a single gland may interact so that Hormone A (androgen) from cell A is modified in cell B to produce Hormone B (estrogens)
• Modification of a precursor molecule of low activity to one of higher activity by successive steps (calcitriol)
• Peptide Hormone can be produced in the circulation itself from a protein precursor (angiotensin)
Hormone DisposalHormone Disposal• Irreversible removal of H is a result of:
• Target cell uptake
• Metabolic degradation
• Urinary excretion
• Biliary excretion
• The sum of all removal processes is expressed as Metabolic Clearance Rate (MCR)
• MCR= mg/min removed / mg/ml of plasma
• K= MCR / volume of distribution
• K is the fractional turnover rate
• The plasma half-life is inversely related to K
Hormone measurementHormone measurement
• The most common and useful method for measuring hormones is RIA (radioimmunoassay)
• Estimate of hormone secretion rate
• (V con – A con) × blood flow
• This is useful in animal modal but not in human
• Production Rate (PR) is suitable in human
• PR is the total amount of the H entering the circulation per unit time
• PR = Plasma con × MCR
• Plasma levels is a valid index of Hormone PR
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