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

Tyrosine kinase ( Tyrosine kinase ( insulin & GHinsulin & GH ) )

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

Steroid HormonesSteroid Hormones

Figure 15.2

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

Steroid family receptorsSteroid family receptors

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

Feedback

Neural

Chronal

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 ?

Endocrine →

Neurocrine →

Paracrine →

Autocrine →

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 TransportHormone Transport

• Free

• Bound to plasma proteins

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

Correlation of tCorrelation of t1/21/2 and MCR and MCR

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

Location of the Major Endocrine GlandsLocation of the Major Endocrine Glands

• The major endocrine glands include:

• Pineal gland, hypothalamus, and pituitary

• Thyroid, parathyroid, and thymus

• Adrenal glands and pancreas

• Gonads – male testes and female ovaries

Figure 15.4