Endocrine secretion and action global overview

Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland The secretory vesicles (brown) contain hormones From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010

Learning Objectives 1.

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Describe the four classes of chemical messengers Define hormone and target tissue Distinguish between endocrine and exocrine glands Compare and contrast the nervous system with the endocrine system Describe the common characteristics of all hormones Define binding protein, bound hormone, and free hormone and discuss the effect of binding proteins on circulating hormone levels 7. List and describe the two chemical categories of hormones 8. Explain the influence of the chemical nature of a hormone on its transport in the blood, its removal from circulation, and its life span 9. Describe the three main patterns of hormone secretion

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Overview of the Endocrine System  Endocrine system uses hormones to transfer information between different tissues  It is a finely regulated machine that uses feedback loops and sensors to ensure constant homeostasis within body  It plays some form of regulatory role in almost all physiologic processes  It has effects on development, growth, metabolism and reproduction and works with almost every organ system, including the nervous and immune system  In contrast to neurotransmitters, which work in synapse between neuron endplate and receptors they act on, hormones are secreted into circulation and can work on tissues far away from source of origin Marc Imhotep Cray, MD

Classes of Chemical Messengers 1. Autocrine chemical messengers An autocrine chemical messenger stimulates the cell that originally secreted it  Examples are those secreted by white blood cells during an infection  Several types WBCs can stimulate their own replication, so that total number of white blood cells increases rapidly 2 Paracrine chemical messengers Paracrine chemical messengers act locally on nearby cells  These chemical messengers are secreted by one cell type into extracellular fluid and affect surrounding cells  An is histamine, released by certain white blood cells during allergic reactions Histamine stimulates vasodilation in nearby blood vessels

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Classes of Chemical Messengers (2) 3 Neurotransmitters Neurotransmitters are chemical messengers secreted by neurons that activate an adjacent cell, whether it is another neuron, a muscle cell, or a glandular cell  NTs are secreted into a synaptic cleft, rather than into bloodstream Therefore, in strictest sense NTs are paracrine agents, but for our purposes it is most appropriate to consider them as a separate category 4 Endocrine chemical messengers Endocrine chemical messengers are secreted into bloodstream by certain glands and cells, which together constitute endocrine system  These chemical messengers travel through general circulation to their target cells Marc Imhotep Cray, MD

The routes by which chemical signals are delivered to cells.

Marc Imhotep Cray, MD

Modified from: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

Autonomic Nervous System vs Endocrine System in Homeostasis Autonomic nervous system (ANS) is the moment-to-moment regulator of the internal environment, regulating specific functions that occur without conscious control:  respiration,  circulation,  digestion,  body temperature,  metabolism,  sweating, secretions of certain endocrine glands Endocrine system, in contrast, provides slower, more generalized regulation by secreting hormones into the systemic circulation to act at distant, widespread sites over periods of minutes to hours to days Marc Imhotep Cray, MD

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ANS and Endocrine System [common properties]   

high-level integration in brain ability to influence processes in distant regions of body extensive use of negative feedback  maintain homeostasis  both systems use chemicals for transmission of information

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Homeostasis  The physiologic process of maintaining an internal environment (ECF environment) compatible with normal health  Autonomic reflexes maintain set points and modulate organ system functions via negative feedback in pursuit of homeostasis

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Homeostasis (2)  A dynamic steady state of constituents in internal environment (ECF) that surrounds and exchanges materials with cells

 Factors homeostatically maintained: (Controlled Variables)  Concentration of nutrient molecules  Concentration of O2 and CO2  Concentration of waste products  pH  Concentration of water, salts, and other electrolytes  Temperature  Volume and pressure Marc Imhotep Cray, MD

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Homeostasis (3) Nervous

Marc Imhotep Cray, MD

versus

Endocrine

Wired

Wireless

Neurotransmitters

Hormones Hormones

Short Distance Short Distance

Long Distance Distance Long

Closeness

Receptor Specificity

Rapid Onset

Delayed Onset

Short Duration

Prolonged Duration

Rapid Response

Regulation

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Components of a negative feedback control system Recognizes deviation of normal set point value

Attempt to restore set point value

Measures control variable

COMPARATOR SENSOR stretch receptors, chemo-, baro-, osmo-, and thermoreceptors etc

+ ERROR SIGNAL

SET POINT

EFFECTOR

CONTROLLED VARIABLE (SEE NEXT SLIDE)

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Negative feedback: Initiation of responses that counter deviations of controlled variables from their normal range

NEGATIVE FEEDBACK Important variable maintained within a normal range

Effector opposes stimulus Redrawn after: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture; McGraw-Hill ,2009:2

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Examples of Physiologic Controlled Variables Controlled Variable

Typical Set Point Value

(Arterial Blood Sample)

Arterial O2 partial pressure Arterial CO2 partial pressure Arterial blood pH Glucose Core body temperature Serum Na+ Serum K+ Serum Ca2+ Mean arterial blood pressure Glomerular filtration rate

100 mm Hg 40 mm Hg pH 74 90 mg/dL (5 mM) 984째F (37째C) 140 mEq/L 40 mEq/L 45 mEq/L 90 mm Hg 120 mL /min

Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology: The Big Picture; McGraw-Hill ,2009:3 Marc Imhotep Cray, MD

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Some Important Negative Feedback Control Systems

From Carroll RG Elsevier’s Integrated Physiology Mosby, Inc. 2007; TABLE 1-3, Pg 5

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Mean Arterial Pressure (MAP) Control and Autonomic & Hormonal Feedback Loops

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Katzung & Trevor Pharmacology Examination & Board Review

10th

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Ed 2014

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Endocrine Glands and Hormones 

Secrete biologically active molecules into blood  Lack ducts

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Carry hormones to target cells that contain specific receptor proteins for that hormone

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Target cells can respond in a specific fashion Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Endocrine Glands and Hormones 

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Neurohormone:  Specialized neurons that secrete chemicals into blood rather than synaptic cleft  Chemical secreted is called neurohormone Hormones:  Affect metabolism of target organs  Help regulate total body metabolism, growth, and reproduction

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Chemical Classification of Hormones 

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Amines:  Hormones derived from tyrosine and tryptophan  NE, Epi, T4 Polypeptides and proteins:  Polypeptides:  Chains of < 100 amino acids in length  ADH  Protein hormones:  Polypeptide chains with > 100 amino acids  Growth hormone

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Chemical Classification of Hormones cont. 

Lipids derived from cholesterol  Are lipophilic hormones  Testosterone  Estradiol  Cortisol  Progesterone

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Glycoproteins:  Long polypeptides (>100) bound to 1 or more carbohydrate (CHO) groups  FSH and LH

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Cholesterol-derived (Steroid) Hormones

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Chemical Classification of Hormones cont. 

Hormones can also be divided into:  Polar:  H20 soluble  Nonpolar (lipophilic):  H20 insoluble  Can gain entry into target cells  Steroid hormones and T4  Pineal gland secretes melatonin:  Has properties of both H20 soluble and lipophilic hormones

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Prohormones and Prehormones 

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Prohormone:  Precursor is a longer chained polypeptide that is cut and spliced together to make the hormone  Proinsulin Preprohormone:  Prohormone derived from larger precursor molecule  Preproinsulin Prehormone:  Molecules secreted by endocrine glands that are inactive until changed into hormones by target cells  T4 converted to T3

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Common Aspects of Neural and Endocrine Regulation 

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APs are chemical events produced by diffusion of ions through neuron plasma membrane Action of some hormones are accompanied by ion diffusion and electrical changes in target cell  Nerve axon boutons release NTs  Some chemicals are secreted as hormones, and also are NTs In order for either a NT or hormone to function in physiological regulation:  Target cell must have specific receptor proteins  Combination of regulatory molecule with its receptor proteins must cause a specific sequence of changes  There must be a mechanism to quickly turn off action of a regulator

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Hormonal Interactions 

Synergistic:  Two hormones work together to produce a result

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Additive:  Each hormone separately produces response, together at same concentrations stimulate even greater effect  NE and Epi

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Complementary:  Each hormone stimulates different step in process  FSH and testosterone

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Hormonal Interactions cont. 

Permissive effects:  Hormone enhances responsiveness of a target organ to second hormone 

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Increases activity of a second hormone  Prior exposure of uterus to estrogen induces formation of receptors for progesterone

Antagonistic effects:  Action of one hormone antagonizes effects of another 

Insulin and glucagon

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Effects of [Hormone] on Tissue Response 

[Hormone] in blood reflects rate of secretion

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Half-life:  Time required for blood [hormone] to be reduced to ½ reference level  Minutes to days

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Normal tissue responses are produced only when [hormone] are present within physiological range

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Varying [hormone] within normal, physiological range can affect responsiveness of target cells

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Effects of [Hormone] on Tissue Response 

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Priming effect (upregulation):  Increase number of receptors formed on target cells in response to particular hormone  Greater response by target cell Desensitization (downregulation):  Prolonged exposure to high [polypeptide hormone] 

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Subsequent exposure to same [hormone] produces less response  Decrease in number of receptors on target cells  Insulin in adipose cells

Pulsatile secretion may prevent downregulation

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Mechanisms of Hormone Action 

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Hormones of same chemical class have similar mechanisms of action  Similarities include:  Location of cellular receptor proteins depends on chemical nature of hormone  Events that occur in target cells To respond to a hormone:  Target cell must have specific receptors for that hormone (specificity)  Hormones exhibit:  Affinity (bind to receptors with high bond strength)  Saturation (low capacity of receptors)

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Hormones that Bind to Nuclear Receptor Proteins 

Lipophilic steroid and thyroid hormones are attached to plasma carrier proteins  Hormones dissociate from carrier proteins to pass through lipid component of target plasma membrane

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Receptors for lipophilic hormones are known as nuclear hormone receptors

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Nuclear Hormone Receptors 

Steroid receptors are located in cytoplasm and in nucleus

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Function within cell to activate genetic transcription 

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Each nuclear hormone receptor has 2 regions:  

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Messenger RNA directs synthesis of specific enzyme proteins that change metabolism A ligand (hormone)-binding domain DNA-binding domain

Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element) 

Located adjacent to gene that will be transcribed

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Mechanisms of Steroid Hormone Action Cytoplasmic receptor binds to steroid hormone Translocates to nucleus DNA-binding domain binds to specific HRE of the DNA Dimerization* occurs Stimulates transcription of particular genes *Dimerization = Process of 2 receptor units coming together at the 2 half-sites.

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Mechanism of Thyroid Hormone Action 

T4 passes into cytoplasm and is converted to T3

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Receptor proteins located in nucleus 

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T3 binds to ligand-binding domain Other half-site is vitamin A derivative (9-cis-retinoic) acid 

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DNA-binding domain can then bind to the half-site of the HRE

Two partners can bind to the DNA to activate HRE 

Stimulate transcription of genes Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Hormones that Use 2nd Messengers 

Hormones that cannot pass through plasma membrane use 2nd messengers 

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Catecholamine, polypeptide, and glycoprotein hormones bind to receptor proteins on target plasma membrane

Actions are mediated by 2nd messengers (signaltransduction mechanisms) 

Extracellular hormones are transduced into intracellular 2nd messengers

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Adenylate Cyclase-cAMP Polypeptide or glycoprotein hormone binds to receptor protein causing dissociation of a subunit of G-protein  G-protein subunit binds to and activates adenylate cyclase  ATP cAMP + PPi  cAMP attaches to inhibitory subunit of protein kinase  Inhibitory subunit dissociates and activates protein kinase 

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Adenylate Cyclase-cAMP 

Phosphorylates enzymes within cell to produce hormone’s effects

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Modulates activity of enzymes present in cell

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Alters metabolism of cell

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cAMP inactivated by phosphodiesterase 

Hydrolyzes cAMP to inactive fragments

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Phospholipase-C-Ca2+ 

Binding of epinephrine to α-adrenergic receptor in plasma membrane activates a G- protein intermediate, phospholipase C 

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Phospholipase C splits phospholipid into IP3 and DAG nd messengers  Both derivatives serve as 2

IP3 diffuses through cytoplasm to ER 

Binding of IP3 to receptor protein in ER causes Ca2+ channels to open

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Phospholipase-C-Ca2+ cont. 

Ca2+ diffuses into cytoplasm 

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Ca2+ binds to calmodulin

Calmodulin activates specific protein kinase enzymes 

Alters metabolism of cell, producing hormone’s effects Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Epinephrine Can Act Through Two 2nd Messenger Systems

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Tyrosine Kinase 

Insulin receptor consists of 2 units that dimerize when they bind with insulin 

Insulin binds to ligand–binding site on plasma membrane, activating enzymatic site in cytoplasm

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Autophosphorylation occurs, increasing tyrosine kinase activity

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Activates signaling molecules  

Stimulate glycogen, fat and protein synthesis Stimulate insertion of GLUT-4 (glucose transporter) carrier proteins

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Tyrosine Kinase cont.

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Pituitary Gland  

Pituitary gland is located in diencephalon Structurally and functionally divided into:  

Anterior lobe Posterior lobe

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Pituitary Gland cont. 

Anterior pituitary(adenohypophysis):  

Master gland Derived from a pouch of epithelial tissue that migrates upward from mouth 

Consists of 2 parts: 

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Pars distalis: anterior pituitary Pars tuberalis: thin extension in contact with the infundibulum

Posterior pituitary (neurohypophysis):  

Formed by downgrowth of brain during fetal development Is in contact with infundibulum  Nerve fibers extend through infundibulum

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Pituitary Hormones 

Anterior Pituitary: 

Trophic effects:  High blood [hormone] causes target organ to hypertrophy 

Low blood [hormone] causes target organ to atrophy Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Pituitary Hormones cont. 

Posterior pituitary: 

Stores and releases 2 hormones that are produced in hypothalamus:  Antidiuretic hormone (ADH/vasopressin):  Promotes retention of H20 by kidneys  Less H20 is excreted in urine  Oxytocin:  Stimulates contractions of uterus during parturition  Stimulates contractions of mammary gland alveoli  Milk-ejection reflex

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Hypothalamic Control of Posterior Pituitary 

Hypothalamus neuron cell bodies produce:  

ADH: supraoptic nuclei Oxytocin: paraventricular nuclei

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Transported along hypothalamo-hypophyseal tract

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Stored in posterior pituitary

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Release controlled by neuroendocrine reflexes

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Hypothalamic Control of Anterior Pituitary 

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Hormonal control rather than neural Hypothalamus neurons synthesize releasing and inhibiting hormones Hormones are transported to axon endings of median eminence Hormones secreted into hypothalamo-hypophyseal portal system regulate secretions of anterior pituitary Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Feedback Control of Anterior Pituitary 

Anterior pituitary and hypothalamic secretions are controlled by target organs they regulate 

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Secretions are controlled by negative feedback inhibition by target gland hormones ( so-called second tier hormones )

Negative feedback at 2 levels: 

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The target gland hormone can act on hypothalamus and inhibit secretion of releasing hormones The target gland hormone can act on anterior pituitary and inhibit response to the releasing hormone

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Feedback Control of Anterior Pituitary cont. 

Short feedback loop: 

Retrograde transport of blood from anterior pituitary to hypothalamus 

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Hormone released by anterior pituitary inhibits secretion of releasing hormone

Positive feedback effect: 

During menstrual cycle, estrogen stimulates LH surge Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Higher Brain Function and Pituitary Secretion 

Axis: 

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Relationship between hypothalamus, anterior pituitary and a particular target gland  Hypothalamic-pituitary-gonad axis

Hypothalamus receives input from higher brain centers 

Psychological stress affects:  Circadian rhythms  Menstrual cycle

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Adrenal Glands 

Paired organs that cap kidneys

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Each gland consists of an outer cortex and inner medulla

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Adrenal medulla: 

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Derived from embryonic neural crest ectoderm (same tissue that produces sympathetic ganglia) Synthesizes and secretes:  Catecholamines (mainly Epi but some NE)

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Functions of Adrenal Medulla 

Innervated by preganglionic sympathetic axons  Increase respiratory rate  Increase HR and cardiac output  Vasoconstrict blood vessels, thus increasing venous return  Stimulate glycogenolysis  Stimulate lipolysis

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Adrenal Glands 

Adrenal cortex: 

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Consists of 3 zones:   

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Does not receive neural innervation Must be stimulated hormonally (ACTH) Zona glomerulosa Zona fasciculata Zona reticularis

Secretes corticosteroids Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Functions of the Adrenal Cortex 

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Zona glomerulosa:  Mineralcorticoids (aldosterone): + +  Stimulate kidneys to reabsorb Na and secrete K Zona fasciculata:  Glucocorticoids (cortisol):  Inhibit glucose utilization and stimulate gluconeogenesis Zona reticularis (DHEA):  Sex steroids:  Supplement sex steroids

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Functions of Adrenal Cortex

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Stress and Adrenal Gland 

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Non-specific response to stress produces general adaptation syndrome (GAS) Alarm phase: 

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Stage of resistance: 

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Adrenal glands activated Stage of readjustment

Stage of exhaustion: 

Sickness and/or death if readjustment is not complete Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Thyroid Hormones 

Thyroid gland is located just below larynx

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Thyroid is largest of pure endocrine glands

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Follicular cells secrete thyroxine

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Parafollicular cells secrete calcitonin

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Production of Thyroid Hormones 

Iodide (I-) actively transported into follicle and secreted into colloid 

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Iodine attached to tyrosine within thyroglobulin chain  

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Oxidized to iodine (Io)

Attachment of 1 iodine produces monoiodotyrosine (MIT) Attachment of 2 iodines produces diiodotyrosine (DIT)

MIT and DIT or 2 DIT molecules coupled together 

T3 and T4 produced

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Production of Thyroid Hormones cont.  

T3 and T4 produced TSH stimulates pinocytosis into follicular cell 

Enzymes hydrolyze T3 and T4 from thyroglobulin



Attached to TBG and released into blood

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Production of Thyroid Hormones

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Actions of T3  

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Stimulates protein synthesis Promotes maturation of nervous system Stimulates rate of cellular respiration by:  Production of uncoupling proteins  Increase active transport by Na+/K+ pumps  Lower cellular [ATP] Increases metabolic heat Increases metabolic rate  Stimulates increased consumption of glucose, fatty acids and other molecules

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Diseases of Thyroid 

Iodine-deficiency (endemic) goiter:  Abnormal growth of thyroid gland  In absence of sufficient iodine, cannot produce adequate amounts of T4 and T3  Lack of negative feedback inhibition  Stimulates TSH, which causes abnormal growth Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Diseases of Thyroid cont. 

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Adult myxedema: (Iodine-deficiency goiter cont.)  Accumulation of mucoproteins and fluid in subcutaneous tissue Symptoms:  Decreased metabolic rate  Weight gain  Decreased ability to adapt to cold  Lethargy

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Diseases of Thyroid cont. 

Grave’s disease:  Autoimmune disorder:  Exerts TSH-like effects on thyroid  Not affected by negative feedback

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Cretinism:  Hypothyroid from end of 1st trimester to 6 months postnatally Severe mental retardation

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Parathyroid Glands 

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Embedded in lateral lobes of thyroid gland Parathyroid hormone (PTH): 

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Only hormone secreted by parathyroid glands

Single most important hormone in control of blood [Ca2+] Stimulated by decreased blood [Ca2+] Promotes rise in blood [Ca2+] by acting on bones, kidney and intestines Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Pancreatic Islets (Islets of Langerhans) 

Alpha cells secrete glucagon   

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Stimulus is decrease in blood [glucose] Stimulates glycogenolysis and lipolysis Stimulates conversion of fatty acids to ketones

Beta cells secrete insulin   

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Stimulus is increase in blood [glucose] Promotes entry of glucose into cells Converts glucose to glycogen and fat Aids entry of amino acids into cells Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011

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Pineal Gland 

Secretes melatonin:  Production stimulated by suprachiasmatic nucleus (SCN) in hypothalamus   

 

SCN is primary center for circadian rhythms Light/dark changes required to synchronize Melatonin secretion increases with darkness and peaks in middle of night

May inhibit GnRH May function in onset of puberty (controversial)

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Pineal Gland

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Thymus 

Site of production of T cells (thymus- dependent cells), which are lymphocytes  Lymphocytes are involved in cell-mediated immunity

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Secretes hormones that are believed to stimulate T cells after leave thymus  Thymus gland size is large in newborns and children  Regresses after puberty and becomes infiltrated with strands of fibrous tissue

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Gonads and Placenta 

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Gonads (testes and ovaries):  Secrete sex hormones  Testosterone  Estradiol 17-β  After menopause, produces estrone  Progesterone Placenta:  Secretes large amounts of estriol, progesterone, hCG, hCS

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Autocrine and Paracrine Regulation 

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Autocrine:  Produced and act within same tissue of an organ  All autocrine regulators control gene expression in target cells Paracrine:  Produced within one tissue and regulate a different tissue of same organ Cytokines (lymphokines):  Regulate different cells (interleukins) Growth factors:  Promote growth and cell division in any organ Neutrophins:  Guide regenerating peripheral neurons

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Prostaglandins    

Most diverse group of autocrine regulators Produced in almost every organ Wide variety of functions Different prostaglandins may exert antagonistic effects in some tissues 

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Immune system:  Promote inflammatory process Reproductive system:  Play role in ovulation Digestive system:  Inhibit gastric secretion

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Prostaglandins

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Prostaglandins cont. 

Respiratory system:  May bronchoconstrict or bronchodilate

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Circulatory system:  Vasoconstrictors or vasodilators

Urinary system:  Vasodilation Inhibitors of prostaglandin synthesis:  Non-steroidal anti-inflammatory drugs (NSAIDS)  Aspirin, indomethacin, ibuprofen: inhibit COX1  Celecoxib : inhibit COX2 

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THE END

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Further study: eLearning Endocrine cloud folder tools and resources Textbooks Fox SI. Human Physiology 12th ed. New York: McGraw-Hill, 2011 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Hall JE. Guyton and Hall Textbook of Medical Physiology, 13Ed. Philadelphia: Elsevier, 2016

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