ENDOCRINE PHYSIOLOGY

I.I. Endocrine and hormoneII.II. Endocrine of h of hypothalamus-pituitary gland and pineal gland *

III.III. Endocrine of thyroid gland **IV.IV. Endocrine of parathyroid gland, thyroid C cell and VitaminD3

V.V. Endocrine of pancreatic islet **•Endocrine of adrenal gland **•Endocrine of tissue hormone and functional organ

What will we discuss in this chapter?What will we discuss in this chapter?(Outline)(Outline)

I.I. Endocrine and hormoneEndocrine and hormone

1. Basic principles and organization1. Basic principles and organization

Definition of the Endocrine SystemDefinition of the Endocrine System•Endocrine and nervous systems coordinate

complex body functions.•Classic distinction between these two is that the

endocrine system communicates to distant tissues through blood-carried chemicals while the nervous system communicates to adjacent tissue by local chemical release (neurotransmitter,

•Organs of the endocrine system include adrenal, gonads, hypothalamus, pancreas, parathyroid, pituitary, thyroid, as well as others, such as the heart, kidney, and gastrointestinal tract.

Distinction between these two Distinction between these two communication systems communication systems

—Nervous system and Endocrine system —Nervous system and Endocrine system

• Nerves in the posterior pituitary release oxytocinNerves in the posterior pituitary release oxytocin and and antidiuretic hormone, which act on the breast and kidneys, antidiuretic hormone, which act on the breast and kidneys, respectively; respectively;

• Nerves release epinephrine from the adrenal medulla, which Nerves release epinephrine from the adrenal medulla, which acts on the heart, skeletal muscle, and the liver;acts on the heart, skeletal muscle, and the liver;

• Nerves of the hypothalamus secrete chemicals (releasing Nerves of the hypothalamus secrete chemicals (releasing hormones) that act on the anterior pituitary to cause hormones) that act on the anterior pituitary to cause hormone release. hormone release.

• Therefore, the definition of the endocrine system should Therefore, the definition of the endocrine system should also include such also include such neuroendocrineneuroendocrine systems. systems.

General definition for hormoneGeneral definition for hormone

•Classic definitionClassic definition ( By Starling and Bayliss) ( By Starling and Bayliss)

The hormones are chemical substances produced by The hormones are chemical substances produced by specialized tissues and secreted into blood, in which they are specialized tissues and secreted into blood, in which they are carried to target organs and triggers specific biological carried to target organs and triggers specific biological functions.functions.

•Limits of classic definition:Limits of classic definition:

Specialized tissues for hormone synthesisSpecialized tissues for hormone synthesis

Blood for hormone distributionBlood for hormone distribution

A separate target organA separate target organ•Broader definitionBroader definition

A hormone is a chemical non-nutrient, intercellular A hormone is a chemical non-nutrient, intercellular messenger that is effective at micromolar concentrations or less messenger that is effective at micromolar concentrations or less (high efficiency).(high efficiency).

•Living things that can secrete homonesLiving things that can secrete homones

Multicelluar: Animal, Plant, Insect and Some fungi.Multicelluar: Animal, Plant, Insect and Some fungi.

•ConcentrationConcentration

Peptidal hormone in animal blood 10Peptidal hormone in animal blood 10-12-12~10~10-10 -10 M,M,

Steroid hormone in animal blood 10Steroid hormone in animal blood 10-10-10~10~10-8 -8 M.M.

•Endocrine cell and Target Cell, tissue and organ.Endocrine cell and Target Cell, tissue and organ.

•Powerful Biological EffectsPowerful Biological Effects

Metabolic and Physiological effect.Metabolic and Physiological effect.

A further understanding on A further understanding on hormoneshormones

TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT

ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT

Hypothalamus Corticotropin-releasing hormone (CRH) Stimulates ACTH secretion

Dopamine Inhibits prolactin secretion

Gonadotropin-releasing hormone (GnRH) Stimulates LH and FSH secretion

Growth-hormone releasing hormone (GHRH) Stimulates GH secretion

Somatostatin Inhibits GH secretion

Thyrotropin-releasing hormone (TRH) Stimulates TSH and prolactin

secretion

Anterior Adrenocorticotropic hormone (ACTH) Stimulates synthesis/secretion

pituitary of cortisol, androgens and

aldosterone

Follicle- stimulating hormone (FSH) Stimulates sperm maturation;

development of ovarian follicles

Growth hormone (GH) Stimulates protein synthesis and

growth

Luteinizing hormone (LH) Stimulates testosterone,

estrogen, progesterone

synthesis; stimulates ovulation

Melanocyte-stimulating hormone (MSH) Stimulates melanin synthesis

Prolactin Stimulates milk production

Thyroid-stimulating hormone (TSH) Stimulates thyroid hormone

synthesis/secretion

Posterior Oxytocin Stimulates milk ejection and

Pituitary uterine contraction

Antidiuretic hormone (ADH) Stimulates renal water

reabsorption

Thyroid Triiodothyronine (T3) and Stimulates growth, oxygen

thyroxine (T4) consumption, heat production,

metabolism, nervous system

development

Continued next

TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT (continued)ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT Thyroid Calcitonin Decreases blood Ca concentration Parathyroid Parathyroid hormone (PTH) Increases blood Ca concentration Adrenal cortex Cortisol Increases glucose synthesis; mediates “stress” response Aldosterone Increases renal reabsorption of Na+, secretion of K+, and H+ Androgens Similar to testosterone but weaker Adrenal medulla Epinephrine Stimulates fat and carbohydrate metabolismPancreas Insulin Decreases blood glucose levels; anabolic effects on lipid and protein metabolism Glucagon Increases blood glucose levels Testes Testosterone Stimulates spermatogenesis and secondary sex characteristics Ovaries Estradiol Stimulates growth/development of female reproductive system and breasts, follicular phase of menstrual cycle, prolactin secretion, and maintains pregnancy Progesterone Luteal phase of menstrual cycle and maintains pregnancy Corpus luteum Estradiol and progesterone See abovePlacenta Human chorionic gonadotropin (hCG) Stimulates estrogen/progesterone synthesis by corpus luteum Human placental lactogen (hPL) Acts like GH and prolactin during pregnancy Estriol Acts like estradiol Progesterone See aboveThis table lists the major endocrine organs, the hormones each organ secretes, and the major tissue effect of the hormone.

Endocrine SystemEndocrine System

2. Chemical Nature of Hormones 2. Chemical Nature of Hormones

•Classic definition of a hormone is a chemical produced by Classic definition of a hormone is a chemical produced by an organ in a small amount that is released into the blood an organ in a small amount that is released into the blood stream to act on cells in a distant tissue.stream to act on cells in a distant tissue.

•This definition needs to be expanded to include chemicals This definition needs to be expanded to include chemicals that have paracrine and autocrine functions.that have paracrine and autocrine functions.

•Hormones are divided into four groups based on chemical Hormones are divided into four groups based on chemical structure: structure:

(1) amines(1) amines ， ， (come from the amino acid tyrosine),(come from the amino acid tyrosine),

(2) peptides(2) peptides ， ， (less than 20 amino acids), (less than 20 amino acids),

(3) small proteins, (3) small proteins, (more than 20 amino acids), (more than 20 amino acids),

(4) steroids(4) steroids ， ， (come from cholesterol).(come from cholesterol).

TABLE MAJOR HORMONES GROUPED BY CHEMICAL STRUCTURE AMINES PEPTIDES PROTEINS STEROIDS

Dopamine Antidiuretic Adrenocorticotropic Aldosterone

hormone (ADH) Hormone (ACTH)

Epinephrine Gonadotropin- releasing Calcitonin Cortisol

hormone (GnRH)

Thyroxine Melanocyte-Stimulating Human chorionic Estradiol

(T4) hormone (MSH) gonadotropin (hCG)

Triiodothy- Oxytocin Human placental Estriol

ronine (T3) lactogen (hPL)

Thyrotropin-releasing Corticotropin-releasing Progesterone

Hormone (TRH) hormone (CRH)

Somatostain Glucagon Testosterone

Growth hormone (GH) 1,25-vitamin D

Growth hormone-releasing hormone (GHRH)

Follicle-stimulating hormone (FSH)

Insulin

Insulin-like growth factor (IGF-1)

Luteinizing hormone (LH)

Parathyroid hormone (PTH)

Prolactin

Thyroid-stimulating hormone (TSH)

This table groups the major hormones according to their chemical composition

Hormone have four groups based on its chemical structureHormone have four groups based on its chemical structure

3. Communication of the hormones3. Communication of the hormonesTelecrine signals

Neurocrine signals

Communication of the hormonesCommunication of the hormones

Endocrine Cell

Endocrine hormone

Blood Flow

Target Cell

Target Cell

Paracrine Hormone

Autocrine Hormone

Paracrine Cell

Autocrine Cell

Target Cell

Paracrine Hormone

Receptor

4. Mechanism of hormone action 4. Mechanism of hormone action • Hormones act through specific receptors that define tissue Hormones act through specific receptors that define tissue

selectivity and response. selectivity and response.

• Receptors for amine, protein, and peptide hormones are located Receptors for amine, protein, and peptide hormones are located on the cell membrane, while those for steroid and thyroid on the cell membrane, while those for steroid and thyroid hormones are within the cell.hormones are within the cell.

• Membrane receptors are of four types based on their signaling Membrane receptors are of four types based on their signaling mechanisms: G protein, tyrosine kinase, guanylyl cyclase, mechanisms: G protein, tyrosine kinase, guanylyl cyclase, cytokine family.cytokine family.

• Steroid and thyroid hormones act through nuclear receptors that Steroid and thyroid hormones act through nuclear receptors that stimulate gene expression. stimulate gene expression.

• Membrane-receptor mediated hormones elicit Membrane-receptor mediated hormones elicit rapid (minutes) rapid (minutes) cellular responses;cellular responses; nuclear-receptor mediated hormones elicit nuclear-receptor mediated hormones elicit slow (hours), long lasting cellular responses (because of slow slow (hours), long lasting cellular responses (because of slow protein degradation).protein degradation).

Four Types of the Membrane Receptors Based on Their Four Types of the Membrane Receptors Based on Their Intracellular Signaling MechanismsIntracellular Signaling Mechanisms

TABLE HORMONES SIGNALING THROUGH MEMBRANE RECEPTORS

G - Protein Receptors Linked to:

Adenylyl Phospho- Tyrosine Kinase Guanylyl Cyclase Cytokine Receptor

Cyclase lipase C Receptors Receptors Family

ACTH, ADH, Insulin, ANP GH,

Calcitonin, GHRH, Insulin-like prolactin

CRH, GnRH, growth

Dopamine Oxytocin, factor-1

Epinephrine, TRH (IGF-1)

FSH,

Glucagons,

hCG,

LH,

MSH,

PTH,

Somatostatin,

TSH

This table groups the major hormones according to their signaling mechanisms.

A combination of hormone and A combination of hormone and receptorreceptor

Hormone

Hormone

Receptor

Receptor

Changes in conformation of hormone combining with receptor

A: Changes in configuration of receptor induced by hormone

B: Changes in configuration of hormone induced by receptor

Labeled UnlabeledUnlabeled

or receptoror receptor

Complex of Hormone and Complex of Hormone and ReceptorReceptor

Labeled

UnlabeledUnlabeled

ComplexComplex

A combination of hormone and A combination of hormone and receptorreceptor

Receptor quantity limit combination of Receptor quantity limit combination of hormone and receptor hormone and receptor

Receptor quantity limit combination of Receptor quantity limit combination of hormone and receptor hormone and receptor

Combination of Ab and Ag

Components of membrane Components of membrane receptorsreceptors

Membrane receptors consist of three components:

(1) an extracellular domain that binds the hormone;

(2) a transmembrane domain that anchors it in the

membrane;

(3) an intracellular domain that couples the receptor

to an intracellular signaling system.

It was evidenced that For the G-protein coupled receptors, the transmembrane domain loops back and forth through the membrane 7 times, while for others it passes through only once. When the hormone stimulates the receptor, an intracellular signaling system is activated that initiates a cascade of cellular events culminating in the hormone response.

The structure of G-proteinThe structure of G-protein

G-protein

Receptor Receptor

Enzyme

The structure of G-protein coupled receptorsThe structure of G-protein coupled receptors

Outside cell

Inside cell

Cell membrane

Carbohydrate group of glycoprotein

Receptor of transmembrane

7 times

Combining position of phosphorylation

Interaction between the hormones, receptors and G-proteins

Basic status Receptor activation

Subunits disassociation

Reactor activation

GTPase

R: receptor; E: enzyme; H: hormone; S: substance; P: product

Signal conductive mechanism of Signal conductive mechanism of G-protein linked membrane receptorsG-protein linked membrane receptors

• G-protein linked receptorsG-protein linked receptors have the characteristic of being linked to have the characteristic of being linked to an intracellular class of proteins called an intracellular class of proteins called G proteins.G proteins.

• G proteins are a cluster of three proteins (subunits) that, when G proteins are a cluster of three proteins (subunits) that, when activated by hormone binding to the extracellular domain of the activated by hormone binding to the extracellular domain of the receptor, cause stimulation of one of two enzymes, receptor, cause stimulation of one of two enzymes, adenylyl cyclase adenylyl cyclase or phospholipase C or phospholipase C..

• Activation of AC leads to the formation of Activation of AC leads to the formation of cyclic adenosine cyclic adenosine monophosphate (cyclic AMP, cAMP)monophosphate (cyclic AMP, cAMP),, and activation of and activation of phospholipase C leads to the formation of phospholipase C leads to the formation of inositol trisphosphate inositol trisphosphate (IP(IP33)) or or diacylglyercerol (DAG or DG)diacylglyercerol (DAG or DG),, or activation of or activation of protein kinase protein kinase

C ( PKC)C ( PKC). .

• These named second messenger molecules initiate a cascade of These named second messenger molecules initiate a cascade of events culminating in the hormone response.events culminating in the hormone response.

Signal transduction mechanism of Signal transduction mechanism of G-protein coupled receptorsG-protein coupled receptors

R: Regulative subunit

C: catalysis subunit

Physiological and Biochemical function

ACTH, Calcitonin, CRH, Dopamine, FSH, Glucagon, hCG, LH, MSH, PTH, Somatostatin, TSH

Cascade of events culminating in Cascade of events culminating in the hormone responsethe hormone response

Effects of Adenylyl Cyclase (AC) ReceptorsEffects of Adenylyl Cyclase (AC) Receptors

Cell membrane

Protein Protein Biological function

Mechanism of hormone acting on membrane receptorH: hormone; R: receptor; GP: G-protein; AC: adenylyl cyclase; PDE: phosphodiesterase; PKr: protein kinase regulative subunit; PKc: protein kinase catalysis subunit

phosphorylation

Signal transduction of G-protein coupled receptorsSignal transduction of G-protein coupled receptors

ACTH, Calcitonin, CRH, Dopamine, Epinephrine, FSH, Glucagon, hCG, LH, MSH, PTH, Somatostatin, TSH

Theory of the second messengersTheory of the second messengersfor G-protein coupled receptorfor G-protein coupled receptor

Cell membrane

Ad

en

yly

l cycla

se

Hormone

Hormone

Horm

one

Inactive protein kinase

Active protein kinase

Protein phosphorylation

Glycogen decomposition

Fat decomposition

Steroid Hormones synthesisSteroid Hormones synthesis

Histone-nucleic acid synthesissynthesis

Nuclein-protein synthesissynthesis

Membrane protein-membrane permeability

Canaliculus secreted movementAC: Adenylyl cyclase;

R: regulative part in the receptor; C: part for reaction

Principle of hormone acting on membrane receptorPrinciple of hormone acting on membrane receptor

AC

Physiological and Biochemical Functions

Second Second MessengerMessenger

Working mechanism of phospholipase C receptorWorking mechanism of phospholipase C receptor

Cell membrane

Hormone (ADH, GHRH, GnRH, OXT, TRH)

Receptor

G-protein

Phospholipase C

Endoplasmic reticulum

Physiological and Biochemical reaction

Signal transduction processes of phospholipid acyl inositolPIP2: phospholipid acyl inositol disphosphate; DG: diacylglyercerol; IP3: inositol trisphosphate; PKC: protein kinase C; CaM: calcium-mediated protein

Second MessengerSecond Messenger

Effects of Guanylyl Cyclase (GC) Effects of Guanylyl Cyclase (GC) ReceptorsReceptors

• The The guanylyl kinase receptorsguanylyl kinase receptors (on the (on the membrane, combined with ANP) have the membrane, combined with ANP) have the enzyme enzyme guanylyl cyclaseguanylyl cyclase as a portion of their as a portion of their intracellular domain. Binding of hormone to the intracellular domain. Binding of hormone to the extracellular domain leads to activation of extracellular domain leads to activation of guanylyl cyclase and the formation of guanylyl cyclase and the formation of cyclic cyclic guanosine monophosphate (cyclic GMP or guanosine monophosphate (cyclic GMP or cGMP)cGMP). This second messenger initiates the . This second messenger initiates the hormone response.hormone response.

Formation and mechanism of several second Formation and mechanism of several second messengersmessengers

Cyclic adenosine monophosphate (cAMP)

Cyclic guanosine monophosphate (cGMP)

Inositol trisphosphate

Regulative subunit

catalysissubunit

Protein kinase A (PKA)

Diacylglyercerol Release

Protein kinase G (PKG)

Protein kinase C (PKC)

PK

(IP3)

R: receptor; Rs: stimulative receptor; Ri: inhibitory receptor; G: G-protein; Gs: stimulative G-protein; Gi: inhibitory G-protein; AC: adenylyl cyclase; GC: guanylyl cyclase; PC: phospholipase C; CaM: calcium-modulated protein; Tn: troponin C. (DG is actually in the cell membrane)

Effects of Tyrosine Kinase (TK) Effects of Tyrosine Kinase (TK) ReceptorsReceptors

• The The tyrosine kinasetyrosine kinase receptors receptors are are distinguished by having an intracellular distinguished by having an intracellular domain that phosphorylates proteins on domain that phosphorylates proteins on specific tyrosine molecules. These specific tyrosine molecules. These tyrosine-phosphorylated proteins act as tyrosine-phosphorylated proteins act as second messengers to initiate a second messengers to initiate a cascade of events leading to hormone cascade of events leading to hormone response.response.

Mechanism of tyrosine kinase Mechanism of tyrosine kinase (TK) receptors(TK) receptors

Cell membrane

Outside cell

Inside cellInactive tyrosine

kinase (TK)

Active tyrosine kinase (TK)

Hormone

Receptors Receptors

Second MessengerSecond Messenger

Insulin, IGF-1

Mechanisms of hormone acting on Mechanisms of hormone acting on membrane receptors membrane receptors (summing-up)(summing-up)

Effects of Cytokine Receptors FamilyEffects of Cytokine Receptors Family

• Cytokine receptor family is distinguished by Cytokine receptor family is distinguished by the fact that receptor (on the membrane, the fact that receptor (on the membrane, combined with GH, Prolactin) activation combined with GH, Prolactin) activation indirectly leads to intracellular protein indirectly leads to intracellular protein tyrosine phosphorylation. Hormone binding to tyrosine phosphorylation. Hormone binding to the extracellular receptor domain enables the the extracellular receptor domain enables the intracellular domain to bind soluble tyrosine intracellular domain to bind soluble tyrosine kinases called kinases called Janus kinases (or JAK Janus kinases (or JAK kinases)kinases).. Binding activates the JAK kinases, Binding activates the JAK kinases, which phosphorylate intracellular proteins and which phosphorylate intracellular proteins and produce the hormone response.produce the hormone response.

Effects of Steroid and Thyroid HormonesEffects of Steroid and Thyroid Hormones

• Steroid and thyroid hormones (primarily TSteroid and thyroid hormones (primarily T33) signal ) signal

through intracellular receptors, which act solely to through intracellular receptors, which act solely to

initiate gene expression. Both hormone types diffuse initiate gene expression. Both hormone types diffuse

through the cell membrane to act on their intracellular through the cell membrane to act on their intracellular

receptors. The receptors are protein molecules that receptors. The receptors are protein molecules that

bind to specific DNA sequences known as bind to specific DNA sequences known as hormone hormone

response elements (HRE).response elements (HRE). The hormone-receptor The hormone-receptor

complex activates the HRE, initiating DNA complex activates the HRE, initiating DNA

transcription leading to protein synthesis.transcription leading to protein synthesis.

Mechanism of Steroid Hormones EffectMechanism of Steroid Hormones Effect

Hormone

Cell membrane

Cytoplasmic receptor

Nuclear membrane

Nuclear receptor

Specific mRNA

Ribosome

New produced protein

1. Structural domain combined with hormone; 2. Structural domain of signal orientation in the nucleus; 3. Structural domain combined with DNA; 4. Structural domain of transcriptional activation

——Theory of the Genes ExpressionsTheory of the Genes Expressions

Mechanism of Steroid Mechanism of Steroid Hormones EffectHormones Effect

Cell membrane Nucleus

Hormone

Receptor

Changes in receptor

configuration

Transcription

Translation

Specific protein

Metabolic reaction

Mechanism of Steroid Hormones EffectMechanism of Steroid Hormones Effect

Mechanisms of TMechanisms of T33 and T and T44 Effects EffectsCell membrane Mitochondria

Nucleus

Nucleus receptor

Transcription Translation

Specific proteinEnzyme

5. General characteristics of 5. General characteristics of hormone actionhormone action

Specific action: one hormone, one target, like one Specific action: one hormone, one target, like one

key, one lock;key, one lock;

Messenger effect: serve as first messenger;Messenger effect: serve as first messenger;

High efficiency High efficiency

Interaction Interaction ：： coordination, confrontation and coordination, confrontation and

permissive action, etc.permissive action, etc.

6. Synthesis of hormones6. Synthesis of hormones

• Peptide and protein hormones are synthesized from amino Peptide and protein hormones are synthesized from amino

acids as prohormones or preprohormones, which are acids as prohormones or preprohormones, which are

subsequently modified and stored in intracellular vesicles subsequently modified and stored in intracellular vesicles

until secreted by exocytosis.until secreted by exocytosis.

• Amine and steroid hormones are synthesized from Amine and steroid hormones are synthesized from

precursor molecules (tyrosine, cholesterol) present in the precursor molecules (tyrosine, cholesterol) present in the

blood.blood.

• Thyroid and steroid hormones are not stored in secretory Thyroid and steroid hormones are not stored in secretory

vesicles, but the amine hormone epinephrine is.vesicles, but the amine hormone epinephrine is.

Synthesis and release of peptide Synthesis and release of peptide and protein hormonesand protein hormones

(Rough ER)

Processes from preprohormone Processes from preprohormone to hormone to hormone

Processes from prohormone to Processes from prohormone to hormonehormone

7. Control of Hormone Release7. Control of Hormone Release

• Most hormones are released in a pulsatile Most hormones are released in a pulsatile

mannermanner with a frequency that varies from with a frequency that varies from

minutes to months and is characteristic of minutes to months and is characteristic of

the hormone.the hormone.

• Hormone release is influenced in part by Hormone release is influenced in part by

positive and negative feedback mechanisms, positive and negative feedback mechanisms,

especially the latter.especially the latter.

Control of hormone secretionControl of hormone secretion(Common Mechanism)(Common Mechanism)

Solid line means positive feedback;

Broken line represents negative feedback

Super short feedback

Short feedback

Long feedback

Other mechanisms: biological rhythmic secretion; nervoue regulation, etc.

Humoral regulation

8. Hormone Transport in the Blood8. Hormone Transport in the Blood• Amine, peptide, and small protein hormones circulate in a free Amine, peptide, and small protein hormones circulate in a free

form in blood because they are water soluble.form in blood because they are water soluble.

• Steroid and thyroid hormones are carried in the blood bound to Steroid and thyroid hormones are carried in the blood bound to

proteins (as carrier, e.g. albumin) because they are water proteins (as carrier, e.g. albumin) because they are water

insoluble.insoluble.

• Protein binding reduces hormones loss through the kidney since Protein binding reduces hormones loss through the kidney since

the protein-hormone complex cannot be filtered.the protein-hormone complex cannot be filtered.

• Only the free form of the hormone can stimulate tissue receptors Only the free form of the hormone can stimulate tissue receptors

because of the capillary endothelium permeability.because of the capillary endothelium permeability.

• Most hormones are removed from the blood by the liver and Most hormones are removed from the blood by the liver and

kidney shortly after being secreted even though their tissue effect kidney shortly after being secreted even though their tissue effect

continues (half-life of hormonecontinues (half-life of hormone ，，

Half-lifeHalf-life of hormone in the blood of hormone in the bloodThe rate at which the amount of hormone in blood decreases is The rate at which the amount of hormone in blood decreases is called its called its half-life.half-life. This is the time it takes the concentration of This is the time it takes the concentration of the hormone to fall to one half of its previous level. Half-lives the hormone to fall to one half of its previous level. Half-lives vary from minutes for the amine hormones to hours for steroid vary from minutes for the amine hormones to hours for steroid and thyroid hormones. and thyroid hormones.

Hormon

e concentration (µg /

L plasma)

Half-lifeHalf-life

II. Endocrine of hypothalamus-pituitary II. Endocrine of hypothalamus-pituitary gland and pineal glandgland and pineal gland

General OrganizationGeneral Organization

•Pituitary gland and hypothalamus function in a coordinated Pituitary gland and hypothalamus function in a coordinated manner to integrate many endocrine glands.manner to integrate many endocrine glands.

•Pituitary gland is located just below the hypothalamus at the base Pituitary gland is located just below the hypothalamus at the base of the brain to which it is connected by a short stalk (named the of the brain to which it is connected by a short stalk (named the infundibuluminfundibulum ，，

•Pituitary is divided into anterior and posterior portions.Pituitary is divided into anterior and posterior portions.

•Secretion of anterior pituitary hormones is under the control of Secretion of anterior pituitary hormones is under the control of hypothalamic releasing hormones.hypothalamic releasing hormones.

•Posterior pituitary hormones are synthesized in hypothalamic Posterior pituitary hormones are synthesized in hypothalamic nerves whose axons end in the posterior pituitary where hormone nerves whose axons end in the posterior pituitary where hormone is released into the blood.is released into the blood.

1. Relationship of hypothalamus and pituitary gland1. Relationship of hypothalamus and pituitary gland

Relationship of Hypothalamus and Relationship of Hypothalamus and Anterior Pituitary GlandAnterior Pituitary Gland

(Releasing hormones)

Relationship of Hypothalamus and Relationship of Hypothalamus and Posterior Pituitary GlandPosterior Pituitary Gland

2. Hypothalamic Hormones Influence 2. Hypothalamic Hormones Influence Anterior Pituitary Hormone SecretionAnterior Pituitary Hormone Secretion

•Many hormones are released from the hypothalamus that control the Many hormones are released from the hypothalamus that control the release of anterior pituitary hormones: TRH, dopamine, GnRH, CRH, release of anterior pituitary hormones: TRH, dopamine, GnRH, CRH, GHRH, somatostatin, etc.GHRH, somatostatin, etc.

(1) thyrotropin-releasing hormone (TRH(1) thyrotropin-releasing hormone (TRH ，， acts on the thyrotrophs and acts on the thyrotrophs and lactotrophs stimulating TSH and prolactin secretion, respectively. lactotrophs stimulating TSH and prolactin secretion, respectively.

(2) Dopamine inhibits lactotroph secretion of prolactin. (2) Dopamine inhibits lactotroph secretion of prolactin.

(3) Gonadotropin hormone-releasing hormone (GnRH(3) Gonadotropin hormone-releasing hormone (GnRH ，， stimulates FSH stimulates FSH and LH secretion from the gonadotrophs.and LH secretion from the gonadotrophs.

(4) Corticotropin-releasing hormone (CRH(4) Corticotropin-releasing hormone (CRH ，， stimulates corticotroph stimulates corticotroph secretion of ACTH. secretion of ACTH.

(5) Growth hormone-releasing hormone (GHRH) and (6) somatostatin(5) Growth hormone-releasing hormone (GHRH) and (6) somatostatin both act on anterior pituitary somatotrophs with GHRH stimulating and both act on anterior pituitary somatotrophs with GHRH stimulating and somatostatin inhibiting GH secretion.somatostatin inhibiting GH secretion.

Hypothalamic regulatory peptides, HRPHypothalamic regulatory peptides, HRP

Hypothalamic Hormones Influence the Pituitary Hypothalamic Hormones Influence the Pituitary Hormone SecretionHormone Secretion

Hypothalamus

Systemic Circulation

Posterior Pituitary

ADH or Oxytocin Trophic

Hormones

Trophic Cells

AnteriorPituitary

ReleasingHormones

VasculatureThe hypothalamus The hypothalamus regulates secretions regulates secretions from both the anterior from both the anterior and posterior pituitary. and posterior pituitary. In the anterior pituitary, In the anterior pituitary, this is accomplished this is accomplished through the release of through the release of hypothalamic-releasing hypothalamic-releasing factors. In the posterior factors. In the posterior pituitary, the secretion pituitary, the secretion are released from are released from nerves that originate in nerves that originate in the hypothalamus.the hypothalamus.

3. Anterior Pituitary Hormones3. Anterior Pituitary Hormones• Seven hormones are secreted by groups of anterior Seven hormones are secreted by groups of anterior

pituitary cell: TSH, FSH, LH, ACTH, MSH, GH, prolactin.pituitary cell: TSH, FSH, LH, ACTH, MSH, GH, prolactin.• Trophic action is the primary effect of anterior pituitary Trophic action is the primary effect of anterior pituitary

hormones.hormones.• Anterior pituitary hormones can be organized into three Anterior pituitary hormones can be organized into three

groups based on chemical and functional similarities: groups based on chemical and functional similarities: TSH, TSH, FSH, LH (same α-chain and different β-chain)FSH, LH (same α-chain and different β-chain); ; ACTH and ACTH and MSH (derived from proopiomelanocortin, POMC)MSH (derived from proopiomelanocortin, POMC); ; GH and GH and prolactin (straight amino acid chain, about 75% same)prolactin (straight amino acid chain, about 75% same)..

• GH is the main regulator of postnatal growth and GH is the main regulator of postnatal growth and development, and prolactin is the major hormone development, and prolactin is the major hormone responsible for milk production.responsible for milk production.

(1) Growth Hormone (GH)(1) Growth Hormone (GH)**• GH is the main regulator of postnatal growth and development. GH is the main regulator of postnatal growth and development.

• GH has effects on metabolism that result from the direct action of GH on GH has effects on metabolism that result from the direct action of GH on target tissue and effects on growth through GH release of target tissue and effects on growth through GH release of insulin-like insulin-like growth factor 1 ( IGF-1growth factor 1 ( IGF-1 ，， primarily from the liver. primarily from the liver.

• GH’s metabolic effects include decreased tissue glucose uptake with a GH’s metabolic effects include decreased tissue glucose uptake with a consequential increase in blood glucose levels; increased fat metabolism consequential increase in blood glucose levels; increased fat metabolism by adipose tissue; and increased tissue amino acid uptake. These by adipose tissue; and increased tissue amino acid uptake. These metabolic effects lead to an increase in lean body mass and to an metabolic effects lead to an increase in lean body mass and to an elevation in blood insulin levels. elevation in blood insulin levels.

• IGF-1 stimulates cell division in many tissues especially bone. Its effect IGF-1 stimulates cell division in many tissues especially bone. Its effect on bone produces linear growth. In addition, IGF-1 stimulates protein on bone produces linear growth. In addition, IGF-1 stimulates protein synthesis facilitated by the increased amino acid uptake produced by synthesis facilitated by the increased amino acid uptake produced by GH. GH.

• Given these normal effects, it follows that GH deficiency during early Given these normal effects, it follows that GH deficiency during early childhood results in a child with a short stature childhood results in a child with a short stature (dandiprat or pygmy,(dandiprat or pygmy, and and excess body fat, while overproduction excess body fat, while overproduction ((acromegalyacromegaly, , results in excess results in excess organ and linear growth organ and linear growth (gigantism(gigantism ，，

Growth Hormone (GH)Growth Hormone (GH)

The Regulation of GH secretionThe Regulation of GH secretion

(IGF-1)

+

The control of GH release occurs at both the hypothalamic and anterior pituitary levelsThe control of GH release occurs at both the hypothalamic and anterior pituitary levels

(2) Prolactin (PRL) (2) Prolactin (PRL) • PRL is the major hormone responsible for milk production PRL is the major hormone responsible for milk production

((lactogenesislactogenesis) and is involved in breast development. ) and is involved in breast development. • PRL secretion is reciprocally controlled through the stimulatory PRL secretion is reciprocally controlled through the stimulatory

actions of TRH (and other yet to be identified hormones) and the actions of TRH (and other yet to be identified hormones) and the inhibitory effect of dopamine. inhibitory effect of dopamine.

• In the nonlactating person, the effect of dopamine dominates so blood In the nonlactating person, the effect of dopamine dominates so blood levels of PRL are low. At puberty in the female, PRL enhances the levels of PRL are low. At puberty in the female, PRL enhances the ability of the elevated levels of estrogen and progesterone to stimulate ability of the elevated levels of estrogen and progesterone to stimulate breast development.breast development.

• During pregnancy, PRL secretion increases, and together with During pregnancy, PRL secretion increases, and together with estrogen and progesterone enhance the development of milk-estrogen and progesterone enhance the development of milk-producing cells in the breast. Despite the high PRL levels, milk producing cells in the breast. Despite the high PRL levels, milk production does not occur because the high levels of estrogen and production does not occur because the high levels of estrogen and progesterone act on the mammary gland to block the lactogenic effect progesterone act on the mammary gland to block the lactogenic effect of PRL. At birth, the mother’s blood levels of PRL, estrogen, and of PRL. At birth, the mother’s blood levels of PRL, estrogen, and progesterone fall. The act of suckling stimulates TRH (or some other progesterone fall. The act of suckling stimulates TRH (or some other factor) and inhibits dopamine release producing a surge of PRL factor) and inhibits dopamine release producing a surge of PRL secretion, which stimulates milk production. secretion, which stimulates milk production.

(3) (3) Melanocyte-stimulating hormone, MSH

• Proopiomelanocortin Proopiomelanocortin • MSHMSH

Stimulate melanocyte forming melanin to Stimulate melanocyte forming melanin to deepen skin color.deepen skin color.

Involved in releasing regulation of GH, Involved in releasing regulation of GH, aldosterone, CRH, insulin, LH, etc.aldosterone, CRH, insulin, LH, etc.

Controlled by MIF (more) and MRF from Controlled by MIF (more) and MRF from hypothalamushypothalamus

MIF: MIF: MRF:MRF:

(4) (4) Trophic hormone

Anterior pituitary also secretes trophic hormone:

• Thyroid-stimulating hormone (TSH)

• Adrenocorticotropic hormone (ACTH)

• Follicle stimulating hormone (FSH)

• Luteinizing hormone (LH)

4. Posterior Pituitary Hormones4. Posterior Pituitary HormonesPosterior pituitary secretes two hormones, oxytocin (OXT) and Posterior pituitary secretes two hormones, oxytocin (OXT) and

antidiuretic hormone (ADH), that are synthesized by nerves in the antidiuretic hormone (ADH), that are synthesized by nerves in the paraventricular and supraoptic nuclei (PVNparaventricular and supraoptic nuclei (PVN and SON) of and SON) of hypothalamus.hypothalamus.

OXT causes milk ejection in response to suckling by stimulating OXT causes milk ejection in response to suckling by stimulating contraction of myoepithelial cells lining the ducts leading to the contraction of myoepithelial cells lining the ducts leading to the nipples. Sensory receptors in the nipples signal the brain and nipples. Sensory receptors in the nipples signal the brain and hypothalamus causing activation of nerve cells of the PVN and hypothalamus causing activation of nerve cells of the PVN and OXT release. In addition, OXT stimulates uterine contraction but OXT release. In addition, OXT stimulates uterine contraction but its role in parturition is unclear. its role in parturition is unclear.

ADH increases water reabsorption by increasing the water ADH increases water reabsorption by increasing the water permeability of the collecting duct of the kidney. Further permeability of the collecting duct of the kidney. Further discussion of its mechanism of action and the control of its discussion of its mechanism of action and the control of its release can be found in Renal Physiology.release can be found in Renal Physiology.

5. Pineal Gland5. Pineal Gland• Pineal gland position: superior posterior part of thalamus

• Synthesis and secretion: melatonin, MLT and vasotocin

• MLT function: Appeasement, hypnosis analgesia Anti-convulsion ; anti-depression;Inhibiting activities of hypothalamus-pituitary gland-target

gland axis; Inhibiting activities of gonads axis;Involved in immunoloregulation;Crucial role in biological rhythm (bioclock) regulation;Regulating visceral activity, such as cardiovascular, renal,

pulmonary, gastrointestinal function.Vasotocin, VAT: inhibiting activities of gonads axis and

ovulation 。

III. Endocrine of thyroid gland III. Endocrine of thyroid gland ****

1. General Organization1. General Organization

• Thyroid gland consists of two lobes, one on either side of Thyroid gland consists of two lobes, one on either side of the trachea just below the cricoid cartilage.the trachea just below the cricoid cartilage.

• Lobes are composed of spherical follicles formed by a Lobes are composed of spherical follicles formed by a single layer of epithelial cells that surround a lumen filled single layer of epithelial cells that surround a lumen filled with a gel-like substance called colloid composed with a gel-like substance called colloid composed primarily of thyroglobulin, the precursor of thyroid primarily of thyroglobulin, the precursor of thyroid hormones. hormones.

• The epithelial cells synthesize and secrete thyroglobulin.The epithelial cells synthesize and secrete thyroglobulin.

Anatomy of thyroid glandAnatomy of thyroid gland

Anatomy and histology of thyroid Anatomy and histology of thyroid glandgland

2. Synthesis of Thyroid Hormone2. Synthesis of Thyroid Hormone

• Synthesis includes steps that occur within the epithelial Synthesis includes steps that occur within the epithelial

cells and colloid of the thyroid gland as well as at the target cells and colloid of the thyroid gland as well as at the target

tissue.tissue.

• Iodine uptake and thyroglobulin synthesis occur within Iodine uptake and thyroglobulin synthesis occur within

epithelial cells.epithelial cells.

• Iodination of thyroglobulin and synthesis of TIodination of thyroglobulin and synthesis of T33 and T and T44 occur occur

within the colloid.within the colloid.

• TT33, most active form of the hormone, is produced from T, most active form of the hormone, is produced from T44 at at

the target tissue.the target tissue.

Synthesis of Thyroid HormoneSynthesis of Thyroid Hormone

Thyroid hormone synthesis and secretion involves processes that Thyroid hormone synthesis and secretion involves processes that occur within follicular epithelial cells and in colloid.occur within follicular epithelial cells and in colloid.

II--: iodide ions; I: iodide ions; I22: iodine; TG: thyroglobulin; MIT: : iodine; TG: thyroglobulin; MIT: monoiodotyrosine; DIT: diiodotyrosine.monoiodotyrosine; DIT: diiodotyrosine.

I-

Na+

I- I2 I2

Thyroid Peroxidase

TG

TG

MIT

+

DIT-T3

-T4

-MIT-DIT

-T3

-T4

-MIT-DIT

TG

TG

+

T3

+T4

Follicle Epithelium ColloidBlood

Pump

Tyrosine

MIT+DIT

T3

DIT+DIT

T4

Synthesis of Thyroid HormoneSynthesis of Thyroid Hormone

Tyrosine can be used for Tyrosine can be used for neurotransmitters synthesisneurotransmitters synthesis

• Stimulation of hormone secretion by TSH causes the Stimulation of hormone secretion by TSH causes the

epithelial cells to engulf small globs of colloid and move epithelial cells to engulf small globs of colloid and move

them into the cell by endocytosis. Within the epithelial cell, them into the cell by endocytosis. Within the epithelial cell,

MIT, DIT, TMIT, DIT, T33, and T, and T44 are secreted into the blood while MIT are secreted into the blood while MIT

and DIT are broken down to I- and tyrosine molecules for and DIT are broken down to I- and tyrosine molecules for

reuse by the epithelial cell.reuse by the epithelial cell.

• Most of the secreted TMost of the secreted T3 3 and Tand T44 are carried in the blood are carried in the blood

bound tobound to thyroxinebinding globulin (TBG thyroxinebinding globulin (TBG, , T T33 is more is more

biologically active than Tbiologically active than T44, but since T, but since T44 synthesis occurs synthesis occurs

more rapidly, more Tmore rapidly, more T44 than T than T33 is secreted. Target tissues is secreted. Target tissues

contain an enzyme, contain an enzyme, 5’-iodinase5’-iodinase that converts T4 to T3. that converts T4 to T3.

3. Releases of Thyroid Hormone3. Releases of Thyroid Hormone

Releases of Thyroid HormoneReleases of Thyroid Hormone

4. Control of Thyroid Hormone 4. Control of Thyroid Hormone Secretion Secretion **

• Secretion is stimulated by TSH, which in turn is

stimulated by TRH.

• TSH stimulates all aspects of thyroid hormone

synthesis and secretion and also has a trophic

effect.

• Elevated blood levels of T3 feed back to the

anterior pituitary thyrotrophs and reduce TSH

secretion.

Control of Thyroid Hormone SecretionControl of Thyroid Hormone Secretion• TRH is release from the hypothalamus which acts on the anterior TRH is release from the hypothalamus which acts on the anterior

pituitary thyrotrophs stimulating TSH release. TSH acts on the thyroid pituitary thyrotrophs stimulating TSH release. TSH acts on the thyroid

gland stimulating every aspect of thyroid hormone synthesis and gland stimulating every aspect of thyroid hormone synthesis and

secretion. TSH increase iodide uptake by follicular cells, iodination of secretion. TSH increase iodide uptake by follicular cells, iodination of

thyroglobulin, formation of MIT and DIT, and endocytosis of colloid. thyroglobulin, formation of MIT and DIT, and endocytosis of colloid.

These actions are mediated through G-protein coupled membrane TSH These actions are mediated through G-protein coupled membrane TSH

receptors on the thyroid gland that stimulate the formation of cyclic AMP receptors on the thyroid gland that stimulate the formation of cyclic AMP

and a cascade of protein phosphorylation steps. With sustained TSH and a cascade of protein phosphorylation steps. With sustained TSH

release, a trophic effect occurs causing thyroid gland enlargement.release, a trophic effect occurs causing thyroid gland enlargement.

• T3 controls its own release through a negative feedback effect on the T3 controls its own release through a negative feedback effect on the

pituitary thyrotrophs. Increasing blood levels of free T3 act on pituitary pituitary thyrotrophs. Increasing blood levels of free T3 act on pituitary

thyrotrophs to decrease their number of TRH receptors. This makes TRH thyrotrophs to decrease their number of TRH receptors. This makes TRH

less effective, decreasing the amount of TSH released and therefore, the less effective, decreasing the amount of TSH released and therefore, the

amount of thyroid hormone secreted. The net effect of this feedback amount of thyroid hormone secreted. The net effect of this feedback

process is to produce a relatively constant blood level of thyroid process is to produce a relatively constant blood level of thyroid

hormones. hormones.

Control of Thyroid Hormone SecretionControl of Thyroid Hormone Secretion

Hypothalamus

Anterior Pituitary (Thyrotrophs)

Thyroid Gland

TRH

TSH

T3

(-)

Thyroid hormone (TThyroid hormone (T33) limits its own secretion by inhibiting TSH ) limits its own secretion by inhibiting TSH release from thyrotroph cells of the anterior pituitary.release from thyrotroph cells of the anterior pituitary.

Control of Thyroid Hormone SecretionControl of Thyroid Hormone Secretion

5. Action of Thyroid Hormones 5. Action of Thyroid Hormones ****• Because TBecause T3 3 acts by inducing DNA transcription, its effects on acts by inducing DNA transcription, its effects on

tissue are the result of protein synthesis, primarily the synthesis tissue are the result of protein synthesis, primarily the synthesis of enzymes (particularly the Na-K-ATPase involved in ion of enzymes (particularly the Na-K-ATPase involved in ion transport).transport).

• Thyroid hormones are required for normal growth throughout life.Thyroid hormones are required for normal growth throughout life.• Thyroid hormones affect basal metabolic rate (BMR, raises the Thyroid hormones affect basal metabolic rate (BMR, raises the

cellular oxygen consumption and heat production), metabolism, cellular oxygen consumption and heat production), metabolism, the cardiovascular system (CO, Ventricular contractility and HR↑), the cardiovascular system (CO, Ventricular contractility and HR↑), and the nervous system (excitability↑).and the nervous system (excitability↑).

• Symptoms of thyroid hormone excess or deficiency can be Symptoms of thyroid hormone excess or deficiency can be predicted from their normal effect (hyperthyroidism , an predicted from their normal effect (hyperthyroidism , an autoimmune disease named Graves’ disease or hypothyroidism, autoimmune disease named Graves’ disease or hypothyroidism, also an autoimmune destruction of the thyroid gland, thyroiditis , also an autoimmune destruction of the thyroid gland, thyroiditis , maybe cretinism (maybe cretinism ( occur).occur).

6. Clinic connection6. Clinic connectionHyperthyroidismHyperthyroidism

HypothyroidismHypothyroidism

CretinismCretinism

IV.IV. Endocrine of parathyroid gland, thyroid C cell Endocrine of parathyroid gland, thyroid C cell and VitaminDand VitaminD33

1. Calcium and phosphate regulation

General ConsiderationGeneral Consideration• Approximately half of the calcium in the blood is ionized, the Approximately half of the calcium in the blood is ionized, the

biologically active form.biologically active form.• Approximately half of the calcium in the blood is bound to Approximately half of the calcium in the blood is bound to

albumin or is complexed with anions such as phosphates and albumin or is complexed with anions such as phosphates and sulfates. sulfates.

• Blood Ca homeostasis produced through the interaction of bones, Blood Ca homeostasis produced through the interaction of bones, kidneys, and small intestine.kidneys, and small intestine.

• Parathyroid hormone, calcitonin, and vitamin D are the three Parathyroid hormone, calcitonin, and vitamin D are the three hormones of Ca homeostasis. hormones of Ca homeostasis.

• Hypercalcemia (depress nerve excitability) is characterized by Hypercalcemia (depress nerve excitability) is characterized by constipation, polyuria, and lethargy; hypocalcemia (increase constipation, polyuria, and lethargy; hypocalcemia (increase nerve excitability) is characterized by spontaneous muscle nerve excitability) is characterized by spontaneous muscle twitching, cramps, tingling, and numbness. twitching, cramps, tingling, and numbness.

Structure of BoneStructure of Bone

Histology of BoneHistology of Bone

Histology of BoneHistology of Bone

2. Parathyroid Gland2. Parathyroid Gland

• Parathyroid gland senses blood Ca levels through Parathyroid gland senses blood Ca levels through

cell surface receptors. cell surface receptors.

• Parathyroid gland secretes PTH (84 amino acids) in Parathyroid gland secretes PTH (84 amino acids) in

response to reduced blood Ca levels (by cAmp-response to reduced blood Ca levels (by cAmp-

induced mechanism).induced mechanism).

• PTH stimulates (1) bones dissolution, (2) renal Ca PTH stimulates (1) bones dissolution, (2) renal Ca

reabsorption, and (3) intestinal Ca absorption.reabsorption, and (3) intestinal Ca absorption.

Function of Parathyroid HormoneFunction of Parathyroid Hormone

3. Vitamin D3. Vitamin D33

• Vitamin D (cholecalciferol) is a steroid obtained from the Vitamin D (cholecalciferol) is a steroid obtained from the

diet or synthesized by the skin (from cholesterol under diet or synthesized by the skin (from cholesterol under

the effect of ultraviolet light).the effect of ultraviolet light).

• Active form of vitamin D (1,25- dihydroxycholecalciferol) Active form of vitamin D (1,25- dihydroxycholecalciferol)

is formed in the kidneys through the action of 1α-is formed in the kidneys through the action of 1α-

hydroxylase.hydroxylase.

• Activity of 1α-hydroxylase is influenced by the blood Activity of 1α-hydroxylase is influenced by the blood

levels of Ca and PTH.levels of Ca and PTH.

• Vitamin D elevates blood levels of both Ca and Vitamin D elevates blood levels of both Ca and

phosphate (from DNA levels) through actions on the phosphate (from DNA levels) through actions on the

small intestines, kidneys, and bone. small intestines, kidneys, and bone.

Function of Vitamin DFunction of Vitamin D33

4. Calcitonin4. Calcitonin ，，

• Calcitonin (32 amino acids) is synthesized by Calcitonin (32 amino acids) is synthesized by

parafollicular cells or C cells of the thyroid gland. parafollicular cells or C cells of the thyroid gland.

• Increased blood Ca levels stimulate calcitonin Increased blood Ca levels stimulate calcitonin

secretion.secretion.

• Calcitonin inhibits osteoclast bone resorption Calcitonin inhibits osteoclast bone resorption

reducing blood Ca levels.reducing blood Ca levels.

• Its physiological function is not well defined.Its physiological function is not well defined.

Function of parathyroid hormone Function of parathyroid hormone and calcitonin and calcitonin (summary)(summary)

V.V. Endocrine of pancreatic islet Endocrine of pancreatic islet ** ** 1. General Organization1. General Organization

• Cells of the endocrine pancreas are organized into clusters Cells of the endocrine pancreas are organized into clusters

called islets of Langerhans.called islets of Langerhans.

• Islets of Langerhans are composed of three cell typesIslets of Langerhans are composed of three cell types －－alpha, beta, and delta—that secret glucagons, insulin, and alpha, beta, and delta—that secret glucagons, insulin, and

somatostatin, respectively.somatostatin, respectively.

• Blood flow from the beta cells carries insulin past the alpha Blood flow from the beta cells carries insulin past the alpha

and delta cells and reduces their secretion of glucagons and delta cells and reduces their secretion of glucagons

and somatostatin, receptively.and somatostatin, receptively.

• Insulin and somatostatin inhibit, while glucagons Insulin and somatostatin inhibit, while glucagons

stimulates, the secretions of other islet cells. stimulates, the secretions of other islet cells.

PancreasPancreas

Histology of pancreasHistology of pancreas

Histology of pancreasHistology of pancreas

2. Insulin2. Insulin ****

• Insulin is synthesized by β-cells from a prohormone. Insulin is synthesized by β-cells from a prohormone.

• Insulin is the hormone of plenty and is released when Insulin is the hormone of plenty and is released when

metabolic supply (primarily glucose) exceeds the needs of metabolic supply (primarily glucose) exceeds the needs of

the body. the body.

• Operating through tyrosine kinase receptors on liver, Operating through tyrosine kinase receptors on liver,

skeletal muscle, and adipose cells, insulin conserves skeletal muscle, and adipose cells, insulin conserves

glucose and increases fat storage and protein synthesis. glucose and increases fat storage and protein synthesis.

• Insulin also helps maintain a low blood K ion level by Insulin also helps maintain a low blood K ion level by

stimulating the Na-K-ATPase pump.stimulating the Na-K-ATPase pump.

(1) Synthesis of Insulin(1) Synthesis of Insulin

Insulin is synthesized from an 86 amino acid prohormone by enzymatically removing a central amino acid string and linking the remaining strands with two disulfide bonds. The final hormone looks like two railroad tracks (amino acid chains) held together by two ties (disulfide bonds). This synthesis occurs within storage vesicles of the β-cells.

(2) Secretion of Insulin(2) Secretion of Insulin

• In response to a meal, insulin secretion is stimulated. In response to a meal, insulin secretion is stimulated. An elevated An elevated blood glucose level is the primary stimulus for insulin secretion.blood glucose level is the primary stimulus for insulin secretion. Glucose binds to its Glucose binds to its glutglut 2-transporter on pancreatic β-cells, which 2-transporter on pancreatic β-cells, which carries it into the cell by facilitated transport. Inside the cell, glucose carries it into the cell by facilitated transport. Inside the cell, glucose metabolism leads to increase ATP levels, which in turn open K-metabolism leads to increase ATP levels, which in turn open K-channels depolarizing the cell and increasing intracellular calcium channels depolarizing the cell and increasing intracellular calcium concentration. Elevated Ca induces fusion of the storage vesicles with concentration. Elevated Ca induces fusion of the storage vesicles with the cell membrane and stimulates insulin release. Fatty acids and the cell membrane and stimulates insulin release. Fatty acids and amino acids also stimulate insulin secretion, presumably through a amino acids also stimulate insulin secretion, presumably through a similar mechanism. Glucagon stimulates insulin secretion by acting similar mechanism. Glucagon stimulates insulin secretion by acting directly through a G- protein linked receptor on β-cells as well as directly through a G- protein linked receptor on β-cells as well as indirectly by elevating blood glucose levels (see next section). On the indirectly by elevating blood glucose levels (see next section). On the other hand, somatostatin inhibits insulin secretion by acting directly other hand, somatostatin inhibits insulin secretion by acting directly on the β-cells and indirectly by reducing the ability of glucagon to on the β-cells and indirectly by reducing the ability of glucagon to stimulate insulin secretion. stimulate insulin secretion.

(3) Function of Insulin (3) Function of Insulin ****

Liver

Glucose Stored as Glycogen

Skeletal muscle

Protein Synthesis

Blood Levels Glucose FallAmino Acids FallFatty Acids FallBlood K ion Fall

Adipose Tissue

Fat Synthesis

Amino Acids

Glucose

Fatty Acids

Insulin reduces blood glucose levels by stimulating glucose uptake into muscle and fat as well as by inhibiting the formation (gluconeogenesis) and release of glucose by the liver.

Function of InsulinFunction of Insulin

Function of InsulinFunction of Insulin

(4) Mechanism of Insulin(4) Mechanism of Insulin

Mechanism of InsulinMechanism of Insulin

Mechanism of InsulinMechanism of Insulin

3. Glucagon3. Glucagon • Glucagon is a single chain of 29 amino acids synthesized by Glucagon is a single chain of 29 amino acids synthesized by

α-cells.α-cells.

• Glucagon acts primarily on the liver to increase and maintain Glucagon acts primarily on the liver to increase and maintain blood glucose levels.blood glucose levels.

• Glucagons secretion is increased in response to falling blood Glucagons secretion is increased in response to falling blood glucose and increasing blood amino acid levels.glucose and increasing blood amino acid levels.

• Glucagon secretion is inhibited by insulin acting directly on Glucagon secretion is inhibited by insulin acting directly on α-cell through the insulin-receptor.α-cell through the insulin-receptor.

• Glucagon restores blood glucose levels by stimulating Glucagon restores blood glucose levels by stimulating glucose synthesis from amino acids and by stimulating fat glucose synthesis from amino acids and by stimulating fat metabolism.metabolism.

• Secretion rates of glucagons and insulin change in opposite Secretion rates of glucagons and insulin change in opposite directions to maintain blood glucose homeostasis. directions to maintain blood glucose homeostasis.

(1) Function of Glucagon(1) Function of GlucagonLiver

Glucose Synthesis & Fatty Acid Metabolism

Blood Levels Glucose RiseAmino Acids Rise

Adipose Tissue

Fat BreakdownAmino AcidsGlucose

Fatty Acids

Glucagon elevates blood glucose levels by stimulating the synthesis of new glucose by the liver from amino acids (gluconeogenesis). In addition, glucagon stimulates the liver to metabolize fatty acids rather than glucose.

(2) Interaction between insulin and glucagon(2) Interaction between insulin and glucagon Glucagon and insulin work together to guard against hypoglycemia Glucagon and insulin work together to guard against hypoglycemia (glucagon) and hyperglycemia (insulin). Glucagons stimulates (glucagon) and hyperglycemia (insulin). Glucagons stimulates breakdown (breakdown (catabolismcatabolism) of fats and proteins so that fatty acids can be ) of fats and proteins so that fatty acids can be used for fuel and amino acids can be converted to glucose used for fuel and amino acids can be converted to glucose (gluconeogenesis) thereby guarding against a fall in blood glucose (gluconeogenesis) thereby guarding against a fall in blood glucose levels. On the other hand, insulin stimulates glucose uptake from the levels. On the other hand, insulin stimulates glucose uptake from the blood and its conversion to fats and glycogen thereby guarding against blood and its conversion to fats and glycogen thereby guarding against excess blood glucose. To maintain this balance, blood levels of excess blood glucose. To maintain this balance, blood levels of glucagon and insulin exhibit a reciprocal relationship with the blood glucagon and insulin exhibit a reciprocal relationship with the blood glucose level determining the balance. In the fed state, insulin levels are glucose level determining the balance. In the fed state, insulin levels are high compared to glucagons levels because the high blood glucose high compared to glucagons levels because the high blood glucose stimulates insulin secretion. In addition, the high insulin levels would stimulates insulin secretion. In addition, the high insulin levels would inhibit glucagon release. However, as blood glucose levels fall during an inhibit glucagon release. However, as blood glucose levels fall during an overnight or a prolonged fast, glucagons secretion increases and overnight or a prolonged fast, glucagons secretion increases and insulin secretion decreases so that glucagons levels exceed insulin insulin secretion decreases so that glucagons levels exceed insulin levels. levels.

Interaction between insulin and glucagonInteraction between insulin and glucagon

Interaction between insulin and glucagonInteraction between insulin and glucagon

Interaction between insulin and glucagonInteraction between insulin and glucagon

4. Somatostatin 4. Somatostatin

• Somatostatin is a peptide hormone released from Somatostatin is a peptide hormone released from

δ-δ-cells. cells.

• Somatostatin acts in a paracrine manner to inhibit Somatostatin acts in a paracrine manner to inhibit

glucagon and insulin secretion locally.glucagon and insulin secretion locally.

• Somatostatin secretion is increased in response Somatostatin secretion is increased in response

to a meal and, therefore, acts to modulate the to a meal and, therefore, acts to modulate the

response of insulin and glucagon to a meal. response of insulin and glucagon to a meal.

5. Diabetes Mellitus 5. Diabetes Mellitus • Diabetes mellitus is a disease of altered insulin function and is in Diabetes mellitus is a disease of altered insulin function and is in

two forms. two forms.

• Type I is primarily due to the inability of β-cells to produce and Type I is primarily due to the inability of β-cells to produce and secrete insulin (autoimmune reaction); type is characterized by Ⅱsecrete insulin (autoimmune reaction); type is characterized by Ⅱmarked resistance of target tissues to insulin (obesity, aging, marked resistance of target tissues to insulin (obesity, aging, various illnesses).various illnesses).

• Metabolic characteristics consist of elevated blood glucose Metabolic characteristics consist of elevated blood glucose levels, elevated blood amino acid levels, and elevated free fatty levels, elevated blood amino acid levels, and elevated free fatty acids leading to formation of ketone bodies and acidemia.acids leading to formation of ketone bodies and acidemia.

• Blood level of K ions is also elevated.Blood level of K ions is also elevated.

• Elevated blood glucose levels lead to osmotic diuresis Elevated blood glucose levels lead to osmotic diuresis (dehydration, polyuria, thirst ).(dehydration, polyuria, thirst ).

• Chronic complications of this metabolic disorder affect the eyes, Chronic complications of this metabolic disorder affect the eyes, the kidneys, the peripheral nervous system, and the vascular the kidneys, the peripheral nervous system, and the vascular system. system.

Blood concentration changes in Blood concentration changes in glucagon, insulin and glucoseglucagon, insulin and glucose

Diabetes MellitusDiabetes Mellitus

Examination of diabetes MellitusExamination of diabetes Mellitus

Mechanism of Diabetes MellitusMechanism of Diabetes Mellitus

Relationship between the blood Relationship between the blood glucose and various hormonesglucose and various hormones

VI. Endocrine of adrenal gland VI. Endocrine of adrenal gland ****

1. General Organization

•The adrenal gland, located above each kidney, is divided into an outer cortex and an inner medulla.

•The adrenal cortex secretes three classes of steroid hormones － mineralocorticoids,glucocorticoids and androgens － each form a different cell layer.

•The adrenal medulla secretes the catecholamines, epinephrine, and norepinephrine.

Anatomy of Adrenal GlandAnatomy of Adrenal Gland

Histology of Adrenal GlandHistology of Adrenal Gland

2. Adrenal Cortex2. Adrenal Cortex

(1) Hormone Synthesis(1) Hormone Synthesis

•Hormones of the cortex are all derived from Hormones of the cortex are all derived from

cholesterol (blood).cholesterol (blood).

•Each cortical layer possesses unique enzymes (P450 Each cortical layer possesses unique enzymes (P450

oxidases) that permit the synthesis of layer-specific oxidases) that permit the synthesis of layer-specific

hormones from the common precursor, pregnenolone.hormones from the common precursor, pregnenolone.

Hormone Synthesis of Adrenal CortexHormone Synthesis of Adrenal Cortex

Hormone Synthesis of Adrenal CortexHormone Synthesis of Adrenal CortexZona Glomerulosa

Cholesterol→Pregnenolone→Progesterone→

11-Deoxycorticosterone→Corticosterone→Aldosterone

Zona FasciculataCholesterol→Pregnenolone→17-Hydroxypregnenolone→

17-Hydroxyprogesterone→11-Deoxycortisol→Cortisol

Zona ReticularisCholesterol→Pregnenolone→

17-Hydroxypregnenolone→Dehyrdroepiandrostrone→Androstenedione

Stimulated by ACTH Stimulated by Angiotensin II & K+

Stimulated by ACTH

Each zone of the adrenal cortex utilizes different enzymes to synthesize specific hormones from cholesterol. ACTH primarily stimulates secretions from the zona fasciculata and reticularis while angiotensin and K ions Ⅱstimulate secretion from the zona glomerulosa.

(2) Control of Adrenal Cortex (2) Control of Adrenal Cortex hormone secretionhormone secretion **

• Secretions of the zona fasciculata and reticularis are under Secretions of the zona fasciculata and reticularis are under

the sole control of the CRH-ACTH axis.the sole control of the CRH-ACTH axis.

• Cortisol secretion from the zona fasciculata is pulsatile with Cortisol secretion from the zona fasciculata is pulsatile with

a diurnal rhythm driven by activity within the brain.a diurnal rhythm driven by activity within the brain.

• Stress stimulates the hypothalamus-pituitary-adrenal axis to Stress stimulates the hypothalamus-pituitary-adrenal axis to

increase cortisol secretion.increase cortisol secretion.

• Cortisol secretion is limited by a negative feedback system Cortisol secretion is limited by a negative feedback system

at the lever of both the hypothalamus and anterior pituitary.at the lever of both the hypothalamus and anterior pituitary.

• Secretion of the zona glomerulosa are affected primarily by Secretion of the zona glomerulosa are affected primarily by

the action of angiotensin and to a lesser extent by K ions Ⅱthe action of angiotensin and to a lesser extent by K ions Ⅱ

and ACTH.and ACTH.

Control of Cortisol secretionControl of Cortisol secretionHypothalamus

CRH

Anterior Pituitary (Corticotrophs)

ACTH

Adrenal Cortex (Zona Fasciculata)

Cortisol

(-)

(-)

Cortisol limits its own secretion at the level of the Cortisol limits its own secretion at the level of the hypothalamus and anterior pituitary.hypothalamus and anterior pituitary.

NNeeggatativive e FFeeeeddbbaackck

Control of Cortisol secretionControl of Cortisol secretion

Circadian Rhythmic changes of Circadian Rhythmic changes of plasma cortisol concentration plasma cortisol concentration

Cortisol secretion is pulsatile with a diurnal variation driven by rhythmic neural activity in the brain that stimulate pulsatile CRH release. Blood levels of cortisol are highest immediately before waking and shortly thereafter. Stress and other stimuli override this pattern by directly increasing CRH-ACTH-cortisol secretion.

(3) Glucocorticoid Action(3) Glucocorticoid Action**** Glucocorticoids (cortisol) are essential for life, and without it, we Glucocorticoids (cortisol) are essential for life, and without it, we

cannot survive.cannot survive.It increases blood glucose levels (especially during starvation, It increases blood glucose levels (especially during starvation,

hypoglycemia, stress and trauma), synthesis in the liver and hypoglycemia, stress and trauma), synthesis in the liver and reduces glucose utilization by muscle and fat cells, inhibiting reduces glucose utilization by muscle and fat cells, inhibiting insulin effect, fat redistribution (buffalo hump, moon facies). insulin effect, fat redistribution (buffalo hump, moon facies).

Glucocorticoids are catabolic and diabetogenic, reduce Glucocorticoids are catabolic and diabetogenic, reduce inflammation (Pinflammation (PGG↓, IL-2↓,His↓5-HT↓T-Cell↓), suppress immune ↓, IL-2↓,His↓5-HT↓T-Cell↓), suppress immune

responses, stimulate gastric acid secretionresponses, stimulate gastric acid secretion and support vascular and support vascular response to catecholamines, etc.response to catecholamines, etc.

Stress response , anti-shock, anti-allergy, anti-poisoning.Stress response , anti-shock, anti-allergy, anti-poisoning.Increase RBF, GFR and renal water falloffIncrease RBF, GFR and renal water falloffWidespread use in the clinic.Widespread use in the clinic.

Glucocorticoid ActionGlucocorticoid ActionLiver

Glucose Synthesis

Skeletal muscle

Protein Breakdown

Blood Levels Glucose RiseAmino Acids RiseFatty Acids Rise

Adipose Tissue

Fat Breakdown

Amino Acids

Glucose

Glycerol Fatty Acids

Cortisol elevates blood glucose levels by stimulating glucose synthesis in the liver from amino acids and glycerol derived from protein and fat breakdown, respectively.

Glucocorticoid ActionGlucocorticoid Action

(4) Androgen Action (4) Androgen Action

• Adrenal androgens play an important role in the female Adrenal androgens play an important role in the female

but not in the male Because it do not contribute but not in the male Because it do not contribute

significantly to testosterone synthesis.significantly to testosterone synthesis.

• In the female, androgens are responsible for the In the female, androgens are responsible for the

development of public and axillary hair and for libido. development of public and axillary hair and for libido.

(5) Pathology of(5) Pathology of Adrenal CortexAdrenal Cortex

• Abnormal adrenocortical secretion can result Abnormal adrenocortical secretion can result

from alterations in the gland itself, the from alterations in the gland itself, the

hypothalamus, or the anterior pituitary.hypothalamus, or the anterior pituitary.

• Abnormalities of the adrenal cortex include Abnormalities of the adrenal cortex include

Addison’s disease , Cushing’s syndrome, and Addison’s disease , Cushing’s syndrome, and

Conn’s syndrome.Conn’s syndrome.

• Abnormalities of the anterior pituitary include Abnormalities of the anterior pituitary include

Cushing’s disease.Cushing’s disease.

Glucocorticoid and ClinicGlucocorticoid and Clinic

In the hospital Exogenous cortisol used for treatment for long time cannot be stopped at once!

Glucocorticoid and ClinicGlucocorticoid and Clinic

Glucocorticoid and ClinicGlucocorticoid and Clinic

Glucocorticoid and ClinicGlucocorticoid and Clinic

Glucocorticoid and ClinicGlucocorticoid and Clinic Addison’s DiseaseAddison’s DiseaseAdrenocortical function deficiencyAdrenocortical function deficiency

Pigment depositPigment deposit

Addison’s disease Addison’s disease usually results from an usually results from an autoimmune destruction of all three layers of the autoimmune destruction of all three layers of the adrenal cortex. The symptoms parallel the loss adrenal cortex. The symptoms parallel the loss of all adrenocortical hormones and include of all adrenocortical hormones and include hypoglycemia and weight loss due to the hypoglycemia and weight loss due to the absence of glucocorticoids as well as increased absence of glucocorticoids as well as increased plasma K and hypotension due to the absence of plasma K and hypotension due to the absence of aldosterone. In the absence of adrenocortical aldosterone. In the absence of adrenocortical hormones there is no negative feedback hormones there is no negative feedback inhibition of ACTH release, causing blood ACTH inhibition of ACTH release, causing blood ACTH levels to be very high. Because MSH is a part of levels to be very high. Because MSH is a part of the ACTH molecule, the high levels of ACTH the ACTH molecule, the high levels of ACTH cause the skin darkening of patients with cause the skin darkening of patients with Addison’s disease.Addison’s disease.

Glucocorticoid and ClinicGlucocorticoid and Clinic Cushing’s Syndrome and DiseaseCushing’s Syndrome and Disease

Adrenocortical function overrunAdrenocortical function overrun

“Full-moon” face

•Cushing’s syndrome is excess production of glucocorticoids. Some of the symptoms include hyperglycemia, muscle wasting, obesity, and hypertension. ACTH levels will be low since there is plenty of cortisol to inhibit its release.

•Cushing’s disease results from oversecretion of ACTH from a pituitary tumor. What distinguishes it from Cushing’s syndrome is that the ACTH levels are elevated. All other symptoms are the same.

Conn’s syndrome results from excess aldosterone from an aldosterone-secreting tumor. Symptoms include increase extracellular fluid volume, hypertension, and reduced blood K levels.

Glucocorticoid and ClinicGlucocorticoid and Clinic Conn’s Conn’s SyndromeSyndrome

3. Adrenal Medulla 3. Adrenal Medulla

• The adrenal medulla is essentially a neuroendocrine organ The adrenal medulla is essentially a neuroendocrine organ that is activated by sympathetic preganglionic nerves. that is activated by sympathetic preganglionic nerves.

• Nerve stimulation results in the release of stored Nerve stimulation results in the release of stored epinephrine (more) and norepinephrine (less) from epinephrine (more) and norepinephrine (less) from chromaffin cells (tyrosine).chromaffin cells (tyrosine).

• Catecholamines have widespread effects (through β-Catecholamines have widespread effects (through β-adrenergic G-protein linked membrane receptors) on the adrenergic G-protein linked membrane receptors) on the cardiovascular system, muscle system, and metabolism cardiovascular system, muscle system, and metabolism (blood glucose levels↑).(blood glucose levels↑).

• Emergency reaction hypothesis Emergency reaction hypothesis

VII. Endocrine of tissue hormone and VII. Endocrine of tissue hormone and functional organfunctional organ

Prostaglandin,PG Prostaglandin,PG Leptin Leptin Atrial natriuretic peptide, ANP Atrial natriuretic peptide, ANP Insulin-Like Growth Factor, IGF Insulin-Like Growth Factor, IGF Gastrointestinal hormone Gastrointestinal hormone Erythropoietin, EPO Erythropoietin, EPO Renin,Renin,Placental hormone Placental hormone …………

NeuropeptideNeuropeptide ，，

Consideration after class

1. Please describe mechanism of hormone action.

2. What are the important adenohypophyseal hormones and their physiological functions?

3. Please describe biological function and secretory regulation of thyroid hormone.

4. Please describe physiological function and secretory regulation of glucocorticoid.

5. Please describe physiological function and secretory regulation of insulin.

6. How many hormones are involved in regulating calcium and phosphorus metabolism and how about their action ?