Endocrine Physiology : regulation and action

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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). environment). Integration and regulation of growth and development. development. Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn. newborn.

Hormones travel via the bloodstream to target cells

Types of cell-to-cell signaling cell-toClassic 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. 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. 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. cell.

 Water soluble hormones are freely soluble in the bloodstream and can travel to their targets without being bound to blood proteins however, proteins 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. granules.  Lipid soluble hormones passively diffuse out of the endocrine cell and become complexed with blood proteins called globulins. 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. receptor.  Some lipid soluble proteins dont have binding proteins, for example, aldosterone. 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 Amine (epinephrine) Amine (thyroid hormone) Peptide/protein Steroids and Vitamin D Class of hormone Water-soluble Lipid soluble Water solube Lipid Soluble Location Cell surface Intracellular Cell surface Intracellular

Second messenger systems

 Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma cell, 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 cellcellsurface receptors

 Second messenger systems include: include:
which catalyzes the  Adenylate cyclase conversion of ATP to cyclic AMP; AMP;  Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides); nucleotides);  Calcium and calmodulin; phospholipase C calmodulin; which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol. glycerol.

Second messenger systems

 Each of these second messenger systems activates a specific protein kinase enzyme. enzyme.
 These include cyclic nucleotide-dependent nucleotideprotein kinases  Calcium/calmodulin-dependent protein kinase, Calcium/calmodulinand protein kinase C which depends on diacyl glycerol binding for activation. activation.
 Protein kinase C activity is further increased by calcium which is released by the action of inositol phosphates. 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 lipidhormones 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 receptorcomplex is then binds to specific DNA sequences called response elements.  These DNA sequences are in the regulatory regions of genes.

Receptors for lipid-soluble lipidhormones reside within the cell

 The receptor-hormone complex binds to the receptorregulatory region of the gene and changes the expression of that gene.  In most cases binding of receptor-hormone receptorcomplex 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 cell

Types of hormones-1 hormones Amine hormones: hormones:

Hormones derived from the amino acid tyrosine. tyrosine.

 These include epinephrine, norepinephrine and thyroid hormone. 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: hormones:
Range from 3 amino acids to hundreds of amino acids in size. size. Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone. hormone. Peptide/protein hormones are water soluble. soluble. Comprise the largest number of hormones hormones perhaps in thousands

Types of hormones-3 hormones Steroid hormones: hormones:

All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. it. All steroid hormones are lipid soluble 1,25-dihydroxy Vitamin D3 is also 25derived 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 postmodified 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 signal. 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, postposttranslationally 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 signaling: sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. need. Key features of this stimulus response system are: are:
y y y y y 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 common: 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 hormone2. substrate-hormone substrate3. mineral-hormone mineral-

SubstrateSubstrate-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

Chronotropic control
Endogenous neuronal rhythmicity rhythmicity Diurnal rhythms, circadian rhythms (growth hormone and cortisol), SleepSleep-wake cycle; seasonal rhythm

Circadian (chronotropic) control

Circadian Clock

Negative feedback effects of cortisol

Feedback control of insulin by glucose concentrations

Inputs to endocrine cells

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. 10% 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

Hormonal measurements
Bioassay an assay system (animal, organ, tissue, cell or enzyme system) is standardized with know amounts of the hormone, a standard curve constructed, and the activity of the unknown determined by comparison example: example: testosterone stimulates growth of prostate gland of immature or castrate rat in a dosedose-dependent manner. Androgen content of unknown sample can be determined by comparison with testosterone. disadvantage: cumbersome and difficult disadvantage: advantage: measures substance with biological activity, not just amount

Original bioassay systems defined the endocrine system

Remove endocrine gland and observe what happened Prepare crude extract from gland, inject back into animal and observe what happened In isolated organ or cell systems, add extract or purified hormonal preparations and measure biological response

Hormonal measurements
Chemical methods
chromatography spectrophotometery

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

Ant ri r it it r
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 ACTH

Secretion of glucocorticoids, androgens and mineralocorticoids to a lesser extent

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

Post rior Pit it r

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

Growth Hormone
Hypothalamus Somatostatin + GHRH

Anterior pituitary gland

GH
Liver IGF-1 Somatomedin Cartilage and bone growth Muscle and other organs: -Protein synthesis and growth Adipose Tissue -lipolysis - release of FFAs Most Tissues glucose utilization -o blood glucose

GH levels and effects are most pronounced during puberty

Metabolic Actions of GH Carbohydrates

Increases Blood Glucose Decreases Peripheral Insulin Sensitivity (is Diabetogenic) Increases Hepatic output of Glucose

Proteins
Increases Tissue Amino Acid (A.A.) Uptake Increases A.A. Incorporation into Protein Decreases Urea Production + Nitrogen Balance

Lipids
Is Lipolytic After long administration can be ketogenic particularly in diabetics

InsulinInsulin-Like Growth Factor

IGF-1 production stimulated by GH. Stimulates growth, is IGFmitogenic

Control of GH Secretion
Stimulation of GH secretion
Blood Glucose
Blood Amino Acids, (Arginine, Leucine) GRH, TRH, ADH, glucagon, dopamine, uncontrolled Diabetes Drugs-Dopamine agonists Drugs ExerciseStress sleep puberty

Inhibition of GH secretion
SRIF, IGF, hypothyroidism Increased Blood Glucose Dopamine antagonists, chlorpromazine Emotional deprivation in children, Aging

Growth hormone disorders

Excess GH
Pre-puberty: gigantism Pre obone growth, > 7 ft. tall

Post-puberty: acromegaly Post Some tissues still grow: cartilage in nose, hands, feet, ridges of eyebrow, chin, tongue Metabolic effects: constant increase in blood sugar, increased insulin type 2 diabetes. Can also increase muscle narrowing of arteries, heart attack

 GH Deficiency
GH, IGF-1 IGF Short stature Metabolic effects

Recombinant human GH (RnGH)

First used to treat GHD Supply of RnGH has made it possible to supply GH for general shortness Metabolic effects: acceleration of puberty, pancreatitis, intercranial hypertension, may risk of leukemia, stroke

Sources of IGF-1 Production IGFIGFIGF-1 primary site of production is Liver

Primarily Controlled by GH

IGFIGF-1 Produced in bone

Controlled by PTH (Parathyroid Hormone) and E2

IGFIGF-2 Produced in Fetus

Controlled by PRL and hPL in fetus

IGFIGF-1 & -2 Metabolic Actions

Regulate Cellular Proliferation (Stimulate) Stimulate Cellular Differentiation Stimulate Cellular Metabolism
Resemble Pro-Insulin in Structure and ProFunction
IGF-1 = 42% structural homology with proIGFproinsulin

Endocrine, Autocrine and Paracrine Functions IGFIGF-2 produced in Fetal TissuesTissuesConverts to IGF-1 in children and IGFadults IGFIGF-1 & -2 act on type I IGF receptors (Tyr Kin)

IGF-1 & -2 Metabolic Actions IGFProfound effects on Bone and Cartilage

Stimulate Chondrocytes (Cartilage forming cells) Are Mitogenic Stimulate Osteoblasts (under PTH and E2) Stimulate collagen formation

 Stimulate Bone Matrix formation

Results of all above:
Increase long bone length in pre-pubescent prechildren increase periosteal growth throughout life increase cartilage growth (chondrocytes) increase bone matrix formation

Mimic Insulin Effects

Minimal effectiveness related to Insulin

IGF-1 & -2 Metabolic Actions IGFEffects Muscle

Increases Muscular proliferation
+DNA, +RNA, +Protein Synthesis

Hypothalamic Effects
Decreases GRH release

IGFIGF-1 & -2 Metabolic Actions

Mimic Insulin Effects
Stimulate Glucose Uptake Stimulate Amino Acid Uptake Cross reactions between Insulin and IGFIGFReceptors
receptor classes are similar and to EGF (Epidermal Growth Factor) receptors

But, Minimal effectiveness related to Insulin

Adr nals
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

Adrenal hormone
Adrenal Medulla
Situated directly atop each kidney and stimulated by the sympathetic nervous system Secretes the catecholamines Epinephrine: elicits a fight or flight
response Increase H.R. and B.P. Increase respiration

 Increase metabolic rate Increase glycogenolysis Vasodilation

Norepinephrine
House keeping system

Adrenal Cortex
Secretes over 30 different steroid hormones (corticosteroids)
Mineralocorticoids
Aldosterone: maintains electrolyte balance

Glucocorticoids
Cortisol: Mobilization of free fatty acids Glucose sparing

Gonadocorticoids
testosterone, estrogen, progesterone

Adrenal glucocorticoids
No effect on growth in normal amounts Cortisol, corticosterone levels o during stress and / or disease to help adapt
Decreases blood glucose uptake into tissues
Antagonizes insulin

 Increases breakdown from tissues

Liver - gluconeogenesis

Increases glucose substrates Enhances fat breakdown Very CATABOLIC (breaks down everything including bone)

AntiAnti-inflammatory agent

Pancreas
Glucose metabolism energy accessibility
insulin (beta cells) glucagon (alpha cells) somatostatin or GHIH (delta cells) amylin (beta cells) -

Insulin
Hormone of Feasting From Pancreas - F cells from Islets of Langerhans Allows glucose to enter the cell
o glucose uptake into tissues Affects glucose transporter

Energy Metabolic Processes

Glycogen synthesis Fat synthesis Protein synthesis

Growth
Children with poorly controlled Type I diabetes often have short stature

Glucagon Hormone of Fasting

Insulin Deficiency
Lipolysis
FFA ketone bodies acidifies blood

Protein breakdown Plasma Glucose

Osmotic diuresis
water excretion q plasma volume q arterial blood pressure q brain blood flow

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

KidneyKidney-

erythropoetin

production of RBCs in bone marrow

Other organs which produce hormones

SkinSkincholecalciferol

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

PlacentaPlacenta-

a bunch of hormones including progesterone and estrogen , human chorionic gonadotropin and others