Chapter 7Chapter 7

(1)

Dee Unglaub Silverthorn, Ph.D.

H ^UMAN P ^HYSIOLOGY H ^UMAN P ^HYSIOLOGY

PowerPoint

^®

Lecture Slide Presentation by

Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University

AN INTEGRATED APPROACH

T H I R D E D I T I O N

Chapter 7 Chapter 7

The Endocrine System

(2)

About this Chapter About this Chapter

• Expand on integration of chemical and nervous coordination

• Form and function of key endocrine glands

• Classification, structure and synthesis of hormones

• Pathways of nervous to endocrine regulation

• How target cells/tissues are impacted

• Some pathologies of the endocrine system

(3)

Summary of the Endocrine System Summary of the Endocrine System

Figure 7-2-1: ANATOMY SUMMARY: Hormones

(4)

(5)

(6)

Summary of the Endocrine System

(7)

Summary of the Endocrine System Summary of the Endocrine System

Figure 7-2-3: ANATOMY SUMMARY: Hormones

(8)

Mechanism of Hormone Action Mechanism of Hormone Action

• Hormones produce one or more of the following cellular changes in target cells

• Alter plasma membrane permeability

• Stimulate protein synthesis

• Activate or deactivate enzyme systems

• Induce secretory activity

• Stimulate mitosis

(9)

Chemical Regulating Systems: Overview Chemical Regulating Systems: Overview

• Pheromones: organism to organism communication

• Hormones: cell to cell communication molecules

• Made in gland(s) or cells

• Transported by blood

• Distant target tissue receptors

• Activates physiological response

(10)

Protein and Polypeptide Hormones:

Synthesis and Release

Protein and Polypeptide Hormones:

Synthesis and Release

(11)

Hormones Hormones

• Three types

• Proteins

• Glycoproteins

• Small peptides

• Large proteins

• Lipids

• Cholesterol derivatives

• Eicosanoids

• Amino acid derivatives (Amine

Hormones)

(12)

• Surface receptor

• Hormone binds

• Transduction

• Enzyme activation

• Open channels

• Second messenger systems

• Synthesis

Protein and Polypeptide Hormone Receptors

(13)

• Made of 1-2 amino acids, derived from tyrosine or tryptophan

• Receptors

• Surface

• Intracellular

• Small size, OH group

• Benzine ring

• Examples

• Thyroxin

• Epinephrine

Amine Hormone Structures and Functions

(14)

Amine Hormone Structures and Functions

(15)

• From cholesterol, lipophilic, enter target cell,

• Cytoplasmic or nuclear receptors (mostly)

• Activate DNA for protein synthesis

• Slower acting, longer half-life

• Examples: cortisol, estrogen &

testosterone

Steroid Hormones: Structure and Action

(16)

• 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 protein

• This interaction prompts DNA transcription to produce mRNA

• The mRNA is translated into proteins, which bring about a cellular effect

Steroid Hormones

(17)

Steroid Hormones: Structure and Action Steroid Hormones: Structure and Action

Figure 7-6: Steroid hormones are derived from cholesterol

(18)

(19)

Steroid Hormones: Structure and Action Steroid Hormones: Structure and Action

Figure 7-7: Steroid hormone action

(20)

• 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

Target Cell Specificity

(21)

• Target cell activation depends on 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 Target Cell Activation

Target Cell Activation

(22)

• Hormones circulate in the blood in two forms –

free or bound

• Steroids and thyroid hormone are attached to plasma proteins

• All others are unencumbered

Hormone Concentrations in the Blood

(23)

• 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

Hormone Concentrations in the Blood

(24)

• Blood levels of hormones:

• Are controlled by negative feedback systems

• Vary only within a narrow desirable range

• Hormones are synthesized and released in response to humoral, neural, and

hormonal stimuli

Control of Hormone Release

(25)

• Stimulus

• Afferent signal

• Integration

• Efferent signal (the hormone)

• Physiological action

• Negative feedback

Endocrine Reflex Pathways: Overview

(26)

• Stimuli

• Stretch

• Glucose

• Insulin levels

• Reflex

• Lower blood glucose

• Reduces stimulus

• Reduces insulin release

Multiple Stimuli for Hormone Release:

Nervous & Endocrine

Multiple Stimuli for Hormone Release:

Nervous & Endocrine

(27)

Endocrine Reflex Pathways: Overview Endocrine Reflex Pathways: Overview

Figure 7-9: Hormones may have multiple stimuli for their release

(28)

Neurohormones: secreted into the Blood by Neurons Neurohormones: secreted into the Blood by Neurons

• Adrenal Medulla–catecholamines

• Hypothalamus to:

• Anterior pituitary

• Trophic Hs

• Growth H.

• Prolactin

• Posterior pituitary

• Vasopressin

• Oxytocin

(29)

Neurohormones: secreted into the Blood by Neurons Neurohormones: secreted into the Blood by Neurons

Figure 7-12: Synthesis, storage, and release of posterior pituitary hormones

(30)

Pituitary-Hypothalamic Relationships:

Posterior Lobe

Pituitary-Hypothalamic Relationships:

Posterior Lobe

• The posterior lobe is a downgrowth of hypothalamic neural tissue

• Has a neural connection with the

hypothalamus (hypothalamic-hypophyseal tract)

• Nuclei of the hypothalamus synthesize oxytocin and antidiuretic hormone (ADH)

• These hormones are transported to the

posterior pituitary

(31)

(32)

The Posterior Pituitary and Hypothalamic Hormones

• Posterior pituitary – made of axons of

hypothalamic neurons, stores antidiuretic hormone (ADH) and oxytocin

• ADH and oxytocin are synthesized in the hypothalamus

• ADH influences water balance

• Oxytocin stimulates smooth muscle contraction in breasts and uterus

• Both use PIP-calcium second-messenger

mechanism

(33)

• Oxytocin is a strong stimulant of uterine contraction

• Regulated by a positive feedback

mechanism to oxytocin in the blood

• This leads to increased intensity of uterine contractions, ending in birth

• Oxytocin triggers milk ejection (“letdown”

reflex) in women producing milk Oxytocin

Oxytocin

(34)

• Synthetic and natural oxytocic drugs are used to induce or hasten labor

• Plays a role in sexual arousal and

satisfaction in males and nonlactating females

Oxytocin

(35)

• ADH helps to avoid dehydration or water overload

• Prevents urine formation

• Osmoreceptors monitor the solute concentration of the blood

• With high solutes, ADH is synthesized and released, thus preserving water

• With low solutes, ADH is not released, thus causing water loss from the body

• Alcohol inhibits ADH release and causes copious urine output

Antidiuretic Hormone (ADH)

(36)

Pituitary-Hypothalamic Relationships:

Anterior Lobe

Pituitary-Hypothalamic Relationships:

Anterior Lobe

• The anterior lobe of the pituitary is an outpocketing of the oral mucosa

• There is no direct neural contact with the

hypothalamus

(37)

Endocrine Control: Three Levels of Integration Endocrine Control: Three Levels of Integration

Figure 7-13: Hormones of the hypothalamic-anterior pituitary pathway

(38)

• The six hormones of the adenohypophysis:

• Are abbreviated as GH, TSH, ACTH, FSH, LH, and PRL

• Regulate the activity of other endocrine glands

• In addition, pro-opiomelanocortin (POMC):

• Has been isolated from the pituitary

• Is enzymatically split into ACTH, beta endorphin, and several Melanocyte

Stimulating Hormones and Lipotropins Adenohypophyseal Hormones

Adenohypophyseal Hormones

(39)

Diagram of the POMC Gene Diagram of the POMC Gene

• Pro-opiomelanocortin (POMC) is a precursor

polypeptide with 241 amino acid residues. POMC is synthesized from the 285-amino-acid-long

polypeptide precursor pre-pro-opiomelanocortin

(pre-POMC), by the removal of a 44-amino-acid-long

signal peptide sequence during translation.

(40)

• The hypothalamus sends a chemical stimulus to the anterior pituitary

• Releasing hormones stimulate the synthesis and release of hormones

• Inhibiting hormones shut off the synthesis and release of hormones Activity of the Adenohypophysis

Activity of the Adenohypophysis

(41)

• The tropic hormones that are released are:

• Thyroid-stimulating hormone (TSH), Thyrotropin

• Adrenocorticotropic hormone (ACTH), Corticotropin

• Follicle-stimulating hormone (FSH), a Gonadotropin

• Luteinizing hormone (LH), a Gonadotropin

• Growth Hormone (GH), Somatotropin

Activity of the Anterior Pituitary (Adenophypophysis)

(42)

• Hypothalamic stimulation–from CNS

• Pituitary stimulation–from hypothalamic trophic Hs

• Endocrine gland stimulation–from pituitary trophic Hs

Endocrine Control: Three Levels of Integration

(43)

Negative Feedback Controls:

Long & Short Loop Reflexes Negative Feedback Controls:

Long & Short Loop Reflexes

Figure 7-14: Negative

feedback loops in the

hypothalamicanterior

pituitary pathway

(44)

Negative Feedback Controls:

Long & Short Loop Reflexes Negative Feedback Controls:

Long & Short Loop Reflexes

(45)

• The largest endocrine gland, located in the anterior neck, consists of two lateral lobes connected by a median tissue mass called the isthmus

• Composed of follicles that produce the glycoprotein thyroglobulin

• Colloid (thyroglobulin + iodine) fills the lumen of the follicles and is the precursor of thyroid hormone

• Other endocrine cells, the parafollicular cells, produce the hormone calcitonin

Thyroid Gland

(46)

(47)

Figure 16.7

Thyroid Gland

(48)

• Thyroid hormone – the body’s major metabolic hormone

• Consists of two closely related iodine- containing compounds

• T 4 – thyroxine; has two tyrosine

molecules plus four bound iodine atoms

• T 3 – triiodothyronine; has two tyrosines with three bound iodine atoms

Thyroid Hormone

(49)

• TH is concerned with:

• Glucose oxidation

• Increasing metabolic rate

• Heat production

• TH plays a role in:

• Maintaining blood pressure

• Regulating tissue growth

• Developing skeletal and nervous systems

• Maturation and reproductive capabilities

Effects of Thyroid Hormone

(50)

• Thyroglobulin is synthesized and discharged into the lumen

• Iodides (I ^– ) are actively taken into the cell, oxidized to iodine (I ₂ ), and released into the lumen

• Iodine attaches to tyrosine, mediated by peroxidase enzymes, forming T ₁

(monoiodotyrosine, or MIT), and T 2

(diiodotyrosine, or DIT)

• Iodinated tyrosines link together to form T 3

and T ₄

• Colloid is then endocytosed and combined with a lysosome, where T and T are

Synthesis of Thyroid Hormone

(51)

Figure 16.8

Synthesis of Thyroid Hormone

(52)

• T 4 and T 3 bind to thyroxine-binding

globulins (TBGs) produced by the liver

• Both bind to target receptors, but T 3 is ten times more active than T ₄

• Peripheral tissues convert T 4 to T 3

• Mechanisms of activity are similar to steroids

• Regulation is by negative feedback

• Hypothalamic thyrotropin-releasing

hormone (TRH) can overcome the negative feedback

Transport and Regulation of TH

(53)

• Produced by somatotropic cells of the anterior lobe that:

• Stimulate most cells, but target bone and skeletal muscle to increase mass

• Promote protein synthesis and encourage the use of fats for fuel

• Most effects are mediated indirectly by somatomedins

• GH is a peptide hormone- 191 amino acids Growth Hormone (GH) or Somatotropin

Growth Hormone (GH) or Somatotropin

(54)

• Antagonistic hypothalamic hormones regulate GH

• Growth hormone–releasing hormone (GHRH) stimulates GH release- aka Somatoliberin or Somatocrinin

• Growth hormone–inhibiting hormone (GHIH) inhibits GH release- aka

Somatostatin

Growth Hormone (GH)

(55)

• GH stimulates liver, skeletal muscle, bone, and cartilage to produce insulin-like

growth factors

• Direct action promotes lipolysis and inhibits glucose uptake

Metabolic Action of Growth Hormone

(56)

Metabolic Action of Growth Hormone

(57)

• Growth H

• Somatomedins

• Thyroxin

• All have

receptors on many tissues

• Stimulate

pathways for growth

Multiple Hormones Can Target a Cell/Tissue Multiple Hormones Can Target a Cell/Tissue

Figure 7-17: A complex endocrine pathway

(58)

• Synergism: multiple stimuli more than additive

• Cortisol +5

• Glucagon +10

• Epinephrine +20 (added = +35)

• Synergistic effect + 140

• Antagonism: Two hormones opposing each other in their function, ie. glucagon opposes insulin

• Permissiveness: need 2nd hormone to get full expression, ie. one hormone enhances target organ’s response to a second

More Impacts on Target Cells

(59)

More Impacts on Target Cells More Impacts on Target Cells

Figure 7-18: Synergism

(60)

Permissive Actions of Thyroid Hormone Permissive Actions of Thyroid Hormone

• Thyroxin (T4) is needed for the function of epinephrine in fatty acid release since

Thyroxin induces synthesis of epinephrine receptor

• Thyroid hormone is also

Permissive (needed) for GH secretion and action

Permissive (needed) for development of central nervous system

(61)

• "no bad hormones – just too much or too little"

• Exogenous medication

• Replaces & exceeds normal

• Cause atrophy of gland

• Hypersecretion: too much

• Tumors or cancer

• Grave's disease- thyroxin

• Hyposecretion: too little

• Goiter – thyroxin

• Diabetes – insulin

Pathologies: Over or Under Production

(62)

• Tropic hormone that stimulates the normal development and secretory activity of the thyroid gland

• Triggered by hypothalamic peptide thyrotropin-releasing hormone (TRH)

• Rising blood levels of thyroid hormones act on the pituitary and hypothalamus to block the release of TSH

Thyroid Stimulating Hormone (Thyrotropin)

(63)

• Stimulates the adrenal cortex to release corticosteroids

• Triggered by hypothalamic corticotropin- releasing hormone (CRH) in a daily rhythm

• Internal and external factors such as fever, hypoglycemia, and stressors can trigger the release of CRH

Adrenocorticotropic Hormone (Corticotropin)

(64)

• Adrenal glands – paired, pyramid-shaped organs atop the kidneys

• Structurally and functionally, they are two glands in one

• Adrenal medulla – nervous tissue that acts as part of the SNS

• Adrenal cortex – glandular tissue derived from embryonic mesoderm

Adrenal (Suprarenal) Glands

(65)

Figure 16.12a

Adrenal Cortex

(66)

• Synthesizes and releases steroid hormones called corticosteroids

• Different corticosteroids are produced in each of the three layers

• Zona glomerulosa – mineralocorticoids (chiefly aldosterone)

• Zona fasciculata – glucocorticoids (chiefly cortisol)

• Zona reticularis – gonadocorticoids (chiefly androgens)

Adrenal Cortex

(67)

(68)

• Regulate the electrolyte concentrations of extracellular fluids

• Aldosterone – most important mineralocorticoid

• Maintains Na ⁺ balance by reducing excretion of sodium from the body

• Stimulates reabsorption of Na ⁺ by the kidneys

Mineralocorticoids

(69)

• Help the body resist stress by:

• Keeping blood sugar levels relatively constant

• Maintaining blood volume and preventing water shift into tissue

• Cortisol provokes:

• Gluconeogenesis (formation of glucose from noncarbohydrates)

• Rises in blood glucose, fatty acids, and amino acids

Glucocorticoids (Cortisol)

(70)

• Excessive levels of glucocorticoids:

• Depress cartilage and bone formation

• Inhibit inflammation

• Depress the immune system

• Promote changes in cardiovascular, neural, and gastrointestinal function Excessive Levels of Glucocorticoids

Excessive Levels of Glucocorticoids

(71)

• Most gonadocorticoids secreted are

androgens (male sex hormones), and the most important one is testosterone

• Androgens contribute to:

• The onset of puberty

• The appearance of secondary sex characteristics

• Sex drive in females

• Androgens can be converted into estrogens after menopause

Gonadocorticoids (Sex Hormones)

(72)

• Made up of chromaffin cells that secrete epinephrine and norepinephrine

• Secretion of these hormones causes:

• Blood glucose levels to rise

• Blood vessels to constrict

• The heart to beat faster

• Blood to be diverted to the brain, heart, and skeletal muscle

Adrenal Medulla

(73)

• Epinephrine is the more potent stimulator of the heart and metabolic activities

• Norepinephrine is more influential on peripheral vasoconstriction and blood pressure

Adrenal Medulla

(74)

Stress and the Adrenal Gland

(75)

Symptoms of Cushing’s Symptoms of Cushing’s

• Facial redness

• Rounding of the face (moon face)

• Unexplained weight gain around belly

• Buffalo hump, or hump on back of neck

• Pink or purple stretch marks

• Thicker or more visible body and facial hair

• Acne

• Muscle weakness

• Extreme fatigue

• Thin and fragile skin that bruises easily

• Depression, anxiety and irritability

• Slow healing of cuts, insect bites and infections

• Bone thinning

• Recurrent infections

• Sleep disturbances, night sweats, awake at midnight or 4 am

• High blood pressure

• Diabetes mellitus

• Irregular or absent menstrual periods in females

(76)

(77)

(78)

Cushing’s Syndrome

Clinical features

Cushing’s Syndrome

Clinical features

• General

• Central obesity

• Proximal muscle weakness

• HTN

• Headaches

• Dermatologic

• Wide purple striae

• Spontaneous ecchymoses

• Facial plethora

• Hyperpigmentation

• Acne, hirsutism

• Fungal skin infections

• Endocrine/Metabolic

• Hypokalemic alkalosis

• Hypokalemia

• Osteopenia

• Hypogonadism

• Glucose intolerance

• Hyperlipidemia

• Hyperhomocysteinemia

• Kidney stones

• Polyuria

• Hypercoagulability

• Neuropsychiatric

• Insomnia

• Depression, frank psychosis

(79)

Cushing’s Syndrome

Clinical features

Cushing’s Syndrome

Clinical features

(80)

Presentation Presentation

Weight Gain

Glucose Intolerance HTN

Hypokalemia

Infections

(81)

Pathologies: Over or Under Production Pathologies: Over or Under Production

Figure 7-19: Negative feedback by exogenous cortisol

(82)

• Gonadotropins – follicle-stimulating

hormone (FSH) and luteinizing hormone (LH)

• Regulate the function of the ovaries and testes

• FSH stimulates gamete (egg or sperm) production

• Absent from the blood in prepubertal boys and girls

• Triggered by the hypothalamic

gonadotropin-releasing hormone (GnRH) during and after puberty

Gonadotropins

(83)

(84)

• Paired ovaries in the abdominopelvic cavity produce estrogens and progesterone

• They are responsible for:

• Maturation of the reproductive organs

• Appearance of secondary sexual characteristics

• Breast development and cyclic changes in the uterine mucosa

Gonads: Female

(85)

• In females

• LH works with FSH to cause maturation of the ovarian follicle

• LH works alone to trigger ovulation (expulsion of the egg from the follicle)

• LH promotes synthesis and release of estrogens and progesterone

Functions of Gonadotropins

(86)

• Testes located in an extra-abdominal sac (scrotum) produce testosterone

• Testosterone:

• Initiates maturation of male reproductive organs

• Causes appearance of secondary sexual characteristics and sex drive

• Is necessary for sperm production

• Maintains sex organs in their functional state

Gonads: Male

(87)

• In males

• LH stimulates interstitial cells of the testes to produce testosterone

• LH is also referred to as interstitial cell- stimulating hormone (ICSH)

Functions of Gonadotropins

(88)

• In females, stimulates milk production by the breasts

• Triggered by the hypothalamic prolactin- releasing hormone (PRH)

• Inhibited by prolactin-inhibiting hormone (PIH)

• Blood levels rise toward the end of pregnancy

• Suckling stimulates PRH release and encourages continued milk production Prolactin (PRL)

Prolactin (PRL)

(89)

• Downregulation – hyperinsulinemia

• Transduction abnormalities

• Testicular feminization syndrome: Cause by a defective receptor for Testosterone

• Pseudohypoparathyroidism: caused by defective G Protein Signal Transduction

• Abnormalities of control mechanisms Pathologies: Due to Receptors

Pathologies: Due to Receptors

(90)

Pathologies: Primary and Secondary Hypersecretion

(91)

• Small gland hanging from the roof of the third ventricle of the brain

• Secretory product is melatonin

• Melatonin is involved with:

• Day/night cycles

• Physiological processes that show

rhythmic variations (body temperature, sleep, appetite)

Pineal Gland

(92)

Pineal Gland and Melatonin

(93)

Circadian Clock

(94)

• Melatonin: Influences body clock &

antioxidant activity

• Other roles need research: SAD (Seasonal Affective Disorder) & sexual behavior (?) Pineal Gland and Melatonin

Pineal Gland and Melatonin

(95)

Pineal Gland and Melatonin Pineal Gland and Melatonin

Figure 7-22-2: The pineal gland

(96)

Recommendations for Jet Lag

(97)

• Endocrine glands throughout body are key to chemical integration and homeostasis

• Protein, polypeptide, amine and a few

steroid hormones are plasma soluble and target membrane

• Surface receptors transduce signals into cell and activate via second messengers

• Most steroid and some amine hormones are lipophilic, can pass into cell, bind on

cytoplasmic or nuclear receptors and activate DNA for protein synthesis

• Hypothalamus, pituitary trophic hormone pathways coordinate endocrine regulation

Summary

Chapter 7Chapter 7

Dee Unglaub Silverthorn, Ph.D.

H UMAN P HYSIOLOGY H UMAN P HYSIOLOGY

PowerPoint

Lecture Slide Presentation by

Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University

AN INTEGRATED APPROACH

T H I R D E D I T I O N

Chapter 7 Chapter 7

The Endocrine System

About this Chapter About this Chapter

• Expand on integration of chemical and nervous coordination

• Form and function of key endocrine glands

• Classification, structure and synthesis of hormones

• Pathways of nervous to endocrine regulation

• How target cells/tissues are impacted

• Some pathologies of the endocrine system

Summary of the Endocrine System Summary of the Endocrine System

Figure 7-2-1: ANATOMY SUMMARY: Hormones

Summary of the Endocrine System

Summary of the Endocrine System

Summary of the Endocrine System Summary of the Endocrine System

Figure 7-2-3: ANATOMY SUMMARY: Hormones

Mechanism of Hormone Action Mechanism of Hormone Action

• Hormones produce one or more of the following cellular changes in target cells

• Alter plasma membrane permeability

• Stimulate protein synthesis

• Activate or deactivate enzyme systems

• Induce secretory activity

• Stimulate mitosis

Chemical Regulating Systems: Overview Chemical Regulating Systems: Overview

• Pheromones: organism to organism communication

• Hormones: cell to cell communication molecules

• Made in gland(s) or cells

• Transported by blood

• Distant target tissue receptors

• Activates physiological response

Protein and Polypeptide Hormones:

Synthesis and Release

Protein and Polypeptide Hormones:

Synthesis and Release

Hormones Hormones

• Three types

• Proteins

• Glycoproteins

• Small peptides

• Large proteins

• Lipids

• Cholesterol derivatives

• Eicosanoids

• Amino acid derivatives (Amine

Hormones)

• Surface receptor

• Hormone binds

• Transduction

• Enzyme activation

• Open channels

• Second messenger systems

• Synthesis

Protein and Polypeptide Hormone Receptors

Protein and Polypeptide Hormone Receptors

• Made of 1-2 amino acids, derived from tyrosine or tryptophan

• Receptors

• Surface

• Intracellular

• Small size, OH group

• Benzine ring

• Examples

• Thyroxin

• Epinephrine

Amine Hormone Structures and Functions

Amine Hormone Structures and Functions

Amine Hormone Structures and Functions

Amine Hormone Structures and Functions

• From cholesterol, lipophilic, enter target cell,

• Cytoplasmic or nuclear receptors (mostly)

• Activate DNA for protein synthesis

• Slower acting, longer half-life

• Examples: cortisol, estrogen &

testosterone

H ^UMAN P ^HYSIOLOGY H ^UMAN P ^HYSIOLOGY