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Chapter 18The Endocrine System

• Endocrine and nervous systems work together

• Endocrine system– hormones released into the bloodstream travel throughout the body– target is usually far from site of synthesis– binds to receptors on or in target– targets = cells throughout the body– results may take hours, but last longer

• Nervous system– certain parts release hormones into blood– rest releases neurotransmitters that excite or inhibit nerve, muscle & gland

cells– results in milliseconds, brief duration of effects

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General Functions of Hormones

• Help regulate:– extracellular fluid

– metabolism

– biological clock

– contraction of cardiac & smooth muscle

– glandular secretion

– some immune functions

• Growth & development• Reproduction

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Endocrine Glands Defined

• Exocrine glands– secrete products into ducts which empty into body

cavities or body surface– sweat, oil, mucous, & digestive glands

• Endocrine glands– secrete products (hormones) into bloodstream– pituitary, thyroid, parathyroid, adrenal, pineal– other organs secrete hormones as a 2nd function

• hypothalamus, thymus, pancreas,ovaries,testes, kidneys, stomach, liver, small intestine, skin, heart & placenta

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• most signals produced by cells within the body bind to receptors that are specific for that signal

• most receptors are found on the cell surface• although some can be found within the cell!• binding of the signal (ligand) to the receptor results in a

series of events (signal transduction) within the cell that changes the cells function– e.g. may change the transcription rate of a gene – effects protein

production

Extracellular Signaling: Mechanisms

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Hormones: Mechanisms of Signaling• hormone producing cell = endocrine cell

– e.g. thyroid, pituitary• Autocrine signaling

– cell responds to the hormone it produces• Paracrine signaling

– local action– local hormone (paracrine hormones) act on neighboring cells– autocrines act on same cell that secreted

them• Endocrine signaling

– circulating hormones (endocrine hormones)

– act on distant targets– travel in blood

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Types of Hormones

• water-soluble

• lipid -soluble

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Lipid-soluble Hormones• Steroids

– lipids derived from cholesterol – made in SER– different functional groups attached to

core of structure provide uniqueness• e.g. cortisol, progesterone, estrogen,

testosterone, aldosterone

• Thyroid hormones– tyrosine ring plus attached iodines– are lipid-soluble

• Retinoic acid– lipids derived from retinol (vitamin A)– regulate proliferation, differentiation and

death of many cell types

• some vitamins can acts a lipid-soluble hormones– e.g. vitamin D

• Nitric oxide (NO)- gas

testosterone aldosterone

cortisol

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• Eicosanoids– prostaglandins or leukotrienes

– derived from arachidonic acid (fatty acid)

– AA is converted either into prostaglandin H or into the leukotrienes

– conversion of AA into prostaglandins is regulated by the COX enzymes

– both act in the inflammatory reaction

• e.g. stimulate smooth muscle cells to contract

• e.g. stimulate nerve cells – pain

Lipid-soluble Hormones

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Water-soluble Hormones• Amine, peptide and protein

hormones– modified amino acids to protein chains

– serotonin, melatonin, histamine, epinephrine, insulin, dopamine

– protein hormones – comprised of one or many polypeptide chains

• insulin, glucagon

– peptide hormones – comprised of chains of amino acids

• e.g. growth hormone, oxytocin

– amine hormones – derived from the amino acids tyrosine or tryptophan

• epinephrine (tyrosine and phenylalanine), serotonin (tryptophan), dopamine (tyrosine)

– can also act as neurotransmitters

insulin

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Action of Lipid-Soluble Hormones: Endogenous signaling

• Hormone must be carried by a transport protein that allows it to dissolve within the aqueous (watery) environment of the blood plasma

• Hormone diffuses through phospholipid bilayer & into cell

• the receptor is located within the cell (cytoplasm or the nucleus)

• binding of H to R results in its translocation into the nucleus

• the H then binds directly to specific sequences within the DNA = response elements

• this binding turns on/off specific genes – activates or inhibits gene transcription

• if turned on - new mRNA is formed & directs synthesis of new proteins

• new protein alters cell’s activity• if turned off – no new protein results

and the cell’s activity is altered

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Action of Lipid-Soluble Hormones

• some lipid-soluble hormone don’t cross the plasma membrane – too large

• therefore they bind with receptors on the cell surface and trigger signaling events within the cells– signal similar to water-soluble hormones– e.g. prostaglandins

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Action of Water-Soluble Hormones• easily travels through the blood - hydrophilic• but cannot diffuse through plasma membrane!• therefore absolutely requires the expression of receptors

on the cell surface – integral membrane proteins that act as first messenger

• the receptor protein activates a series of signaling events within the cells

– e.g. epinephrine binds to receptor and activates an adjacent G-protein in membrane

– G-protein activates adenylate cyclase to convert ATP to cyclic AMP (cAMP) in the cytosol

– cAMP is the 2nd messenger– cAMP activates a series of proteins in the cytosol

called kinases– kinases act to phosphorylate their targets – either

activating them or inhibiting them– this speeds up/slows down physiological responses

within the cell– phosphodiesterase inactivates cAMP quickly

• many second messengers are made in cells in response to specific hormones

– e.g. calcium, IP3, DAG• Cell response is turned off unless new hormone

molecules arrive• this mechanism allows for amplification – one H-R

combination can activate two G proteins which activates 4 kinases which activate 16 more kinases etc…….

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Hormonal Interactions• Permissive effect

– a second hormone, strengthens the effects of the first– thyroid strengthens epinephrine’s effect upon lipolysis

• Synergistic effect– two hormones acting together for greater effect– estrogen & LH are both needed for oocyte production

• Antagonistic effects– two hormones with opposite effects– insulin promotes glycogen formation & glucagon

stimulates glycogen breakdown

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Control of Hormone Secretion

• Regulated by signals from nervous system, chemical changes in the blood or by other hormones

• Negative feedback control (most common)– decrease/increase in blood level is reversed

• Positive feedback control– the change produced by the hormone causes

more hormone to be released

• Disorders involve either hyposecretion or hypersecretion of a hormone

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Hypothalamus and Pituitary Gland

• Both are master endocrine glands since their hormones control other endocrine glands

• Hypothalamus is a section of brain above where pituitary gland is suspended from stalk

• Hypothalamus receives input from cortex, thalamus, limbic system & internal organs

• Hypothalamus controls pituitary gland with 9 different releasing & inhibiting hormones

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•hypothalamus-Emotions, autonomic functions, hormone production-mamillary bodies – serve as relay stations for reflexes related to smell-supraoptic and preoptic regions that function in vision-major functions:1. control of the ANS – integrates signals from the ANS (regulated smooth and cardiac muscle contraction) major regulator of visceral activities (heart rate, food movements, contraction of bladder)2. produces hormones & connects with pituitary to regulate its activity

3. regulates emotional and behavioral patterns – rage,aggression, pain and pleasure + sexual arousal4. regulates eating & drinking – hypothalamus contains a thirst center which responds to a rise in osmotic pressure in the ECF (dehydration)5. controls body temperature – monitors temp of bloodflowing through the hypothalamus

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• regulates the activity of the pituitary through its secretion of specific releasing and inhibiting hormones

– e.g. pituitary hormone = somatotropin– hypothalmic hormones = somatotropin

releasing hormone (SRH) and somatotropin inhibiting hormone (SIH)

• also secretes two specific hormones that are stored in the pituitary – oxytocin and anti-diuretic hormone (ADH)

• cells secrete at least 9 different hormones• portion that marks the connection with the

pituitary = median eminence– near the ME is a group of cells =

neurosecretory cells– secrete the hypothalmic releasing and

inhibiting hormones that regulate the pituitary– stored in synaptic vesicles– released upon production of an action potential

via exocytosis

median eminence

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Pituitary Gland

• Pea-shaped, 1/2 inch gland found in sella turcica of sphenoid

• Infundibulum attaches it to brain

• Anterior lobe = 75% develops from roof of mouth

• Posterior lobe = 25%– ends of axons of 10,000 neurons found in

hypothalamus

– neuroglial cells called pituicytes

-hypothalamic hormones(releasing hormones) reach thepituitary via a portal system ofcapillaries = hypophyseal portalsystem (HPS)-flow of blood from the hypothal.into portal veins that carry blood tothe capillaries of the ant pituitary-superior hypophyseal arteries arebranches off of the internal carotid--bring blood into the hypothal.-where the hypothal. and infundibulummeet they divide into the primaryplexus of the HPS-from this plexus blood drains intohypophyseal portal veins-at the anterior pituitary these portalveins divide into the secondary plexusof the HPS-release of the hypothalmic releasing &inhibiting hormones into the primaryplexus of the HPS and travel to the secondary plexus

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• 5 types of cells:• somatotrophs: secrete

hGH/somatotropin

• thyrotrophs: secrete TSH/thyrotropin

• gonadotrophs: secrete FSH, LH

• lactotrophs: secrete prolactin

• corticotrophs: secrete ACTH/corticotropin & MSH

Hormones:human growth hormone- hGHthyroid stimulating - TSHfollicle stimulating- FSHleutinizing hormone - LHprolactinadrenocorticotropin - ACTHmelanocyte stimulating - MSH

Anterior Pituitary

Gland

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• first level of regulation: releasing and inhibiting hormones of the hypothalamus

• second level is negative feedback by hormones release by the target gland– e.g. corticotropin (ACTH) release

stimulated by CRH/corticotropin releasing hormone

– travels to anterior pituitary and stimulates release of ACTH

– ACTH travels to the adrenal gland – stimulates production and secretion of cortisol

– increase of cortisol beyond the normal range triggers release of CIH/corticotropin inhibiting hormone

– CIH shuts down the secretion of ACTh by the anterior pituitary

Anterior Pituitary Gland: Control of Secretion

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Human Growth Hormone• Produced by somatotrophs• release is stimulated by GHRH from the hypothalamus• promotes synthesis of insulin-like growth factors or somatomedins

– common target cells for this synthesis are liver, skeletal muscle, cartilage and bone cells– increases cell growth & cell division by increasing their uptake of amino acids & synthesis of

proteins– stimulates lipolysis in adipose so fatty acids can be used for ATP– stimulates release of glucose into the blood by the liver– retards use of glucose for ATP production so blood glucose levels remain high enough to supply

brain– hGH secretion is promoted by decreased fatty acids and amino acids in the blood, decreased

blood sugar, deep sleep, increased activity by the sympathetic NS, hormones (glucagon, estrogen, cortisol and insulin)

• Excess of growth hormone– raises blood glucose concentration

– pancreas releases insulin continually

– beta-cell burnout

– Diabetogenic effect: causes diabetes mellitis if no insulin activity can occur eventually

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Regulation of hGH• Low blood sugar stimulates

release of GHRH from hypothalamus– anterior pituitary releases

more hGH, more glycogen broken down into glucose by liver cells

• High blood sugar stimulates release of GHIH from hypothalamus– less hGH from anterior

pituitary, glycogen does not breakdown into glucose

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Thyroid Stimulating Hormone (TSH)

• Hypothalamus regulates thyrotroph cells

• Thyrotroph cells produce TSH

• TSH stimulates the synthesis & secretion of T3 and T4

• Metabolic rate stimulated

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Follicle Stimulating Hormone (FSH)

• Releasing hormone from hypothalamus controls gonadotrophs

• Gonadotrophs release follicle stimulating hormone

• FSH functions – initiates the formation of follicles within the ovary– stimulates follicle cells to secrete estrogen– stimulates sperm production in testes

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Luteinizing Hormone (LH)

• Releasing hormones from hypothalamus stimulate gonadotrophs

• Gonadotrophs produce LH

• In females, LH stimulates– secretion of estrogen– ovulation of 2nd oocyte from ovary– formation of corpus luteum– secretion of progesterone

• In males, stimulates interstitial cells to secrete testosterone

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Prolactin (PRL)

• Hypothalamus regulates lactotroph cells

• Lactotrophs produce prolactin

• Under right conditions, prolactin causes milk production

• Suckling reduces levels of hypothalamic inhibition and prolactin levels rise along with milk production

• Nursing ceases & milk production slows

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Adrenocorticotrophic Hormone

• Hypothalamus releasing hormones stimulate corticotrophs

• Corticotrophs secrete ACTH & MSH

• ACTH stimulates cells of the adrenal cortex that produce glucocorticoids

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Melanocyte-Stimulating Hormone

• Secreted by corticotroph cells

• Releasing hormone from hypothalamus increases its release From the anterior pituitary

• Function not certain in humans (increase skin pigmentation in frogs )

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Posterior Pituitary Gland (Neurohypophysis)

• Does not synthesize hormones

• Consists of axon terminals of hypothalamic neurons

• Neurons release two neurotransmitters that enter capillaries– antidiuretic hormone– oxytocin

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Oxytocin• Two target tissues both involved in neuroendocrine

reflexes

• During delivery– baby’s head stretches cervix

– hormone release enhances uterine muscle contraction

– baby & placenta are delivered

• After delivery– suckling & hearing baby’s cry stimulates milk ejection

– hormone causes muscle contraction & milk ejection

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Antidiuretic Hormone (ADH)• Known as vasopressin

• Functions– decrease urine production– decrease sweating– increase BP

• Dehydration– ADH released

• Overhydration– ADH inhibited

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Pituitary Gland Disorders

• Hyposecretion during childhood = pituitary dwarfism (proportional, childlike body)

• Hypersecretion during childhood = giantism– very tall, normal proportions

• Hypersecretion as adult = acromegaly– growth of hands, feet, facial features & thickening of skin

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The peripheral endocrine glands

• thyroid and parathyroid

• adrenal glands

• ovaries and testes

• pancreas

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Thyroid Gland

• comprised of microscopic sacs called follicles = follicular cells making up the walls, surrounds a lumen

• synthesize T3 & T4 (thyroxin)• In between follicular cells cells are

parafollicular cells– produce calcitonin

•On each side of trachea is lobe of thyroid•connected by an isthmus•Weighs 1 oz & has rich blood supply

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Formation of Thyroid Hormone• Iodide trapping: follicular cells actively take up

iodine from blood• Synthesis of thyroglobulin (TGB): RER of follicular

cells make TGB - secreted into the follicle lumen as the material colloid

• Iodination of colloid: iodine ions are oxidated (I2- -> I2) by perioxidase, iodine then binds onto tyrosine residues on the TGB within colloid– this oxidation is required because negatively charges

ions can’t bind onto the tyrosine amino acids

• Coupling of T1 and T2: forms T3 & T4– T2 + T2 = T4; T1 + T2 = T3

• Uptake of colloid by follicular cells: colloid reenters the follicular cells by pinocytosis, merge with lysozymes– digestion of TGB cleaves off T3 and T4 hormones

• Secretion of T3 & T4 into blood: T3 & T4 are transported in blood bound to thryoxine-binding globulin (TBG)

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Actions of Thyroid Hormones

• T3 & T4 = increases metabolic rate

stimulates synthesis of protein

stimulates breakdown of fats

stimulates cholesterol excretion

increases use of glucose & oxygen

(ATP production)

increases body temperature (calorigenic effect)

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Control of T3 & T4 Secretion

• Low blood levels of hormones stimulate hypothalamus -> TRH

• It stimulates pituitary to release TSH

• TSH stimulates thyroid gland to raise blood levels of T3 and T4

• T3 and T4 regulate themselves through a negative feedback loop

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Thyroid disorders

-hyperthyroidism:-most common form – Grave’s disease

• 7 to 10 times more common in females• autoimmune disorder• antibodies that mimic the action of TSH• enlargened thyroid and exophthalmos (edema behind the eyes)

hypothyroidism: reduced production of TSH and thryoid hormones-common treatment – oral L-thyroxin- can produce myxedema in the adult

• more common in females• edema within the facial tissues, slow heart rate, low body temperature

• congenital hypothyroidism– causes severe mental retardation and stunted bone growth– babies appear normal due to maternal thyroid hormones – so testing is required

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Parathyroid Glands

• 4 pea-sized glands found on back of thyroid gland

• Principal cells (chief cells) produce parathyroid hormone (PTH)

• Oxyphil cell function is unknown

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Parathyroid Hormone• Raises blood calcium levels (also regulates Mg and

phosphate levels– increases activity of osteoclasts, increases # of OCs

• releases calcium and HPO4 into the blood– acts on the kidneys to increase reabsorption of Ca+2 back into

the blood (also same for Mg)• increases loss of HPO4 into the urine – decreases the overall level of

HPO4 in the blood– promotes formation of calcitriol (vitamin D3) by kidney which

increases absorption of Ca+2 and Mg+2 by intestinal tract• Opposite function of calcitonin (CT = thyroid)• High or low blood levels of Ca+2 stimulate the release of different

hormones --- PTH or CT– high level of calcium in blood - release of calcitonin by parafollicular cells,

promotes uptake of calcium into bone matrix, lowers blood calcium– low level of calcium in blood - release of PTH by parathyroid glands,

promotes release of calcium from bone, raises blood calcium

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Adrenal Glands

• One on top of each kidney• 3 x 3 x 1 cm in size and weighs 5 grams• Cortex produces 3 different types of

hormones from 3 zones of cortex: mineralcorticoids (aldosterone), glucocorticoids (cortisol) & androgens

• Medulla produces epinephrine & norepinephrine

• Cortex derived from mesoderm

• Medulla derived from ectoderm

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AdrenalGland

• Cortex– 3 zones

• Medulla

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Mineralocorticoids• from the zona glomerulosa of the adrenal

cortex

• 95% of these hormones - aldosterone

• Functions– increase reabsorption of Na+ with Cl- ,

bicarbonate and water following it

– promotes excretion of K+ and H+

• dehydration, hemorrhage (decrease in blood volume) - decreases blood pressure - secretion of renin from kidneys which stimulates angiotensin II release from lungs - stimulates aldosterone release from adrenal cortex - increases water and Na uptake from kidneys and increased excretion of K+ and H+ into urine

• the increase water reabsorption back into the blood increases blood volume and pressure

• angiotensin II also stimulates contraction of smooth muscle within arterioles

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Glucocorticoids• from the zona fasciulata of the adrenal

cortex• 95% of hormonal activity is due to cortisol• neurosecretory cells secrete corticotropin-

releasing hormone (CRH)• CRH promotes the release of ACTH which

stimulates the adrenal cortex to secrete cortisol

• Functions = helps regulate metabolism – increases rate of protein catabolism &

lipolysis (new protein synthesis)– conversion of amino acids to glucose– stimulates lipolysis (glucose synthesis)– provides resistance to stress by making

nutrients available for ATP production (increased glucose synthesis)

– raises BP by vasoconstriction (decreases blood loss)

– anti-inflammatory effects reduced (skin cream)

• reduces release of histamine from mast cells• decreases capillary permeability• depresses phagocytosis

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Androgens

• Small amount of male hormone produced by the zona reticularis– insignificant in males– may contribute to sex drive in females– secreted as dehydroepiandrosterone (DHEA)– is converted to estrogen in postmenopausal females– also used by body builders since it is a precursor to

functional testosterone• high dose administration to be useful – side effects?

– http://skepdic.com/dhea.html– http://en.wikipedia.org/wiki/Dehydroepiandrosterone

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Adrenal Medulla• modified sympathetic ganglion – part of the ANS!• the cells lack axons are cluster around blood vessels• these hormone producing cells = Chromaffin cells

receive direct innervation from sympathetic nervous system

• Produce epinephrine & norepinephrine• Hormones are sympathomimetic

– effects mimic those produced by sympathetic NS– cause fight-flight behavior

• sympathetic preganglionic neurons secrete acetylcholine - which stimulates secretion by the adrenal medulla

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Cushing’s Syndrome• Hypersecretion of glucocorticoids

• Redistribution of fat, spindly arms & legs due to muscle loss

• Wound healing is poor, bruise easily

Addison’s disease

• Hypersecretion of glucocorticoids– hypoglycemia, muscle weakness, low BP, dehydration due to decreased

Na+ in blood

– mimics skin darkening effects of MSH

– potential cardiac arrest

Adrenal Gland disorders

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Pancreas

• Organ (5 inches) consists of head, body & tail• Cells (99%) in acini produce digestive enzymes• Endocrine cells in pancreatic islets produce hormones• Exocrine acinar cells surround a small duct = digestive

enzymes

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• Endocrine cells secrete near a capillary

• 1 to 2 million pancreatic islets

• Contains 4 types of endocrine cells

• Alpha cells (20%) produce glucagon• Beta cells (70%) produce insulin• Delta cells (5%) produce somatostatin• F cells produce pancreatic polypeptide

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Regulation of Glucagon & Insulin Secretion

• Low blood glucose stimulates release of glucagon

• High blood glucose stimulates secretion of insulin

18-51

Diabetes Mellitus & Hyperinsulinism

• Diabetes mellitus marked by hyperglycemia– excessive urine production (polyuria)– excessive thirst (polydipsia)– excessive eating (polyphagia)

• Type I----deficiency of insulin (under 20)

• Type II---adult onset– drug stimulates secretion of insulin by beta cells– cells may be less sensitive to hormone

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Ovaries and Testes

• Ovaries– estrogen, progesterone, relaxin & inhibin– regulate reproductive cycle, maintain pregnancy &

prepare mammary glands for lactation

• Testes– produce testosterone– regulate sperm production & 2nd sexual

characteristics

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Pineal Gland• Small gland attached to 3rd ventricle of

brain

• Consists of pinealocytes & neuroglia

• Melatonin responsible for setting of biological clock

• Jet lag & SAD treatment is bright light

• Melatonin secretion produces sleepiness - occurs during darkness due to lack of stimulation from sympathetic ganglion

•light strikes retina and stimulatessuprachiasmatic region ofhypothalamusstimulates sympathetic ganglionwhich then stimulates thepineal glandlight -> NE -> no melatonindark -> lack of NE -> melatonin

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Thymus Gland

• Important role in maturation of T cells

• Hormones produced by gland promote the proliferation & maturation of T cells– thymosin– thymic humoral factor– thymic factor– thymopoietin

18-55

The stress response

• helpful stress = eustress• stressor = any disturbance in the homeostatic balance of

the human body• when homeostasis can counteract these stressors the body

remains within normal physiologic parameters• if not – a series of reactions occurs = stress response

– three stages:• 1. initial fight or flight response• 2. slower resistance reaction• 3. exhaustion

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• fight or flight– initiated by nerve impulses of

the hypothalamus to the adrenal medulla (ANS)

– release of epinephrine and norepinephrine

– prepares the body for immediate physical response

– short lived response• resistance

– initiated by hypothalmic releasing hormones

– CRH, GHRH and TRH– helps the body continue fighting

the stressor– if the body fails to combat the

stressor, our body enters the last stage

• exhaustion– resources become depleted so

they can no longer continue the resistance stage

– prolonged exposure to cortisol can cause wasting of skeletal muscle, suppression of the immune system, ulceration of the GI tract and failure of the beta cells of the pancreas to make insulin (diabetes)

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Stress and Disease

• can lead to specific diseases by temporarily inhibiting the immune system

• includes gastritis, ulcerative colitis, irritable bowel syndrome, migraines, anxiety, hypertension, asthma, rheumatoid arthritis

• role for interleukin-1 (IL-1) which is secreted by macrophages in the immune system

• IL-1 can stimulate secretion of ACTH by the anterior pituitary– causes production of cortisol– increased resistance to stress – good– BUT if not controlled – exhaustion – bad!

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Eicosanoids• Local hormones released by all body cells• synthesized from arachidonic acid• Leukotrienes influence WBCs & inflammation• Prostaglandins alter

– smooth muscle contraction, glandular secretion, blood flow, platelet function, nerve transmission, metabolism etc.

– Ibuprofen & other nonsteroidal anti-inflammatory drugs treat pain, fever & inflammation by inhibiting prostaglandin synthesis

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Nonsteroidal Anti-inflammatory Drugs

• Answer to how aspirin or ibuprofen works was discovered in 1971– inhibit a key enzyme in prostaglandin synthesis

(COX) without affecting the synthesis of leukotrienes

• Treat a variety of inflammatory disorders– rheumatoid arthritis

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Aging and the Endocrine System• Production of human growth hormone decreases

– muscle atrophy

• Production of TSH increase with age to try and stimulate thyroid – decrease in metabolic rate, increase in body fat & hypothyroidism

• Thymus after puberty is replaced with adipose• Adrenal glands produce less cortisol & aldosterone• Receptor sensitivity to glucose declines• Ovaries no longer respond to gonadotropins

– decreased output of estrogen (osteoporosis & atherosclerosis)