ENDOCRINE PHYSIOLOGY

ENDOCRINE GLANDSENDOCRINE GLANDS

BASIC PRINCIPLES AND BASIC PRINCIPLES AND ORGANIZATIONORGANIZATION

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 antidiuretic hormone, which act on the breast and antidiuretic hormone, which act on the breast and kidneys, respectively; and kidneys, respectively;

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

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

• Therefore, the definition of the endocrine system Therefore, the definition of the endocrine system should also include such should 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 The hormones are chemical substances produced by specialized tissues and secreted into blood, in by specialized tissues and secreted into blood, in which they are carried to target organs and triggers which they are carried to target organs and triggers specific biological functions.specific biological 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 messenger that is effective at micromolar concentrations or less (high efficiency).concentrations or less (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

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

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

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

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

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

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

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

Definition of the hormonesDefinition of the hormonesTelecrine signals

Neurocrine signals

Definition of the hormonesDefinition 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

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

Mechanism of Hormone Action Mechanism of Hormone Action • Hormones act through specific receptors that define Hormones act through specific receptors that define

tissue selectivity and response. tissue selectivity and response. • Receptors for amine, protein, and peptide hormones Receptors for amine, protein, and peptide hormones

are located on the cell membrane, while those for are located on the cell membrane, while those for steroid and thyroid hormones are within the cell.steroid and thyroid hormones are within the cell.

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

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

• Membrane-receptor mediated hormones elicit Membrane-receptor mediated hormones elicit rapid rapid (minutes) cellular responses;(minutes) cellular responses; nuclear-receptor nuclear-receptor mediated hormones elicit mediated hormones elicit slow (hours), long lasting slow (hours), long lasting cellular responses (because of slow protein cellular responses (because of slow protein degradation).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 have the characteristic of being linked to an intracellular class of proteins called linked to an intracellular class of proteins called G proteins.G proteins.

• G proteins are a cluster of three proteins (subunits) that, G proteins are a cluster of three proteins (subunits) that, when activated by hormone binding to the extracellular when activated by hormone binding to the extracellular domain of the receptor, cause stimulation of one of two domain of the receptor, cause stimulation of one of two enzymes, enzymes, adenylyl cyclase (adenylyl cyclase ( 腺苷环化酶腺苷环化酶 AC) or phospholipase CAC) 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 inositol trisphosphate (IPtrisphosphate (IP33)) or or diacylglyercerol (DAG or DG)diacylglyercerol (DAG or DG),, or or

activation of activation of protein kinase C (protein kinase C ( 蛋白激酶蛋白激酶 C, PKC)C, PKC). .

• These named second messenger molecules initiate a cascade These named second messenger molecules initiate a cascade of events culminating in the hormone response.of 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 guanylyl kinase receptors (on the membrane, combined with ANP) have the enzyme guanylyl cyclase （尿苷酸激酶） as a portion of their intracellular domain. Binding of hormone to the extracellular domain leads to activation of guanylyl cyclase and the formation of cyclic guanosine monophosphate (cyclic GMP or cGMP). This second messenger initiates the 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 （酪氨酸激酶）（酪氨酸激酶） receptors receptors are distinguished by having are distinguished by having an intracellular domain that an intracellular domain that phosphorylates proteins on specific phosphorylates proteins on specific tyrosine molecules. These tyrosine-tyrosine molecules. These tyrosine-phosphorylated proteins act as second phosphorylated proteins act as second messengers to initiate a cascade of messengers to initiate a cascade of events leading to hormone response.events leading to hormone 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 kinases)Janus kinases (or JAK kinases).. Binding activates the JAK kinases, which Binding activates the JAK kinases, which phosphorylate intracellular proteins and 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 through intracellular receptors, which signal through intracellular receptors, which act solely to initiate gene expression. Both act solely to initiate gene expression. Both hormone types diffuse through the cell hormone types diffuse through the cell membrane to act on their intracellular membrane to act on their intracellular receptors. The receptors are protein receptors. The receptors are protein molecules that bind to specific DNA molecules that bind to specific DNA sequences known as sequences known as hormone response hormone response elements (elements ( 激素反应元件激素反应元件 HRE).HRE). The hormone- The hormone-receptor complex activates the HRE, receptor complex activates the HRE, initiating DNA transcription leading to initiating DNA transcription leading to protein synthesis.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

Synthesis and Release of HormonesSynthesis and Release of Hormones

• Peptide and protein hormones are synthesized Peptide and protein hormones are synthesized from amino acids as prohormones or from amino acids as prohormones or preprohormones, which are subsequently preprohormones, which are subsequently modified and stored in intracellular vesicles until modified and stored in intracellular vesicles until secreted by exocytosis.secreted by exocytosis.

• Amine and steroid hormones are synthesized from Amine and steroid hormones are synthesized from precursor molecules (tyrosine, cholesterol) precursor molecules (tyrosine, cholesterol) present in the blood.present in the blood.

• Thyroid and steroid hormones are not stored in Thyroid and steroid hormones are not stored in secretory vesicles, but the amine hormone secretory vesicles, but the amine hormone epinephrine is.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

Control of Hormone ReleaseControl of Hormone Release

• Most hormones are released in a Most hormones are released in a pulsatile mannerpulsatile manner （脉冲式） （脉冲式） with a with a frequency that varies from minutes frequency that varies from minutes to months and is characteristic of the to months and is characteristic of the hormone.hormone.

• Hormone release is influenced in part Hormone release is influenced in part by positive and negative feedback by positive and negative feedback mechanisms, especially the latter.mechanisms, 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

Hormone Transport in the BloodHormone Transport in the Blood• Amine, peptide, and small protein hormones circulate in a Amine, peptide, and small protein hormones circulate in a

free form in blood because they are water soluble.free form in blood because they are water soluble.• Steroid and thyroid hormones are carried in the blood Steroid and thyroid hormones are carried in the blood

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

• Protein binding reduces hormones loss through the kidney Protein binding reduces hormones loss through the kidney since the protein-hormone complex cannot be filtered.since the protein-hormone complex cannot be filtered.

• Only the free form of the hormone can stimulate tissue Only the free form of the hormone can stimulate tissue receptors because of the capillary endothelium receptors because of the capillary endothelium permeability.permeability.

• Most hormones are removed from the blood by the liver Most hormones are removed from the blood by the liver and kidney shortly after being secreted even though their and kidney shortly after being secreted even though their tissue effect continues (half-life of hormonetissue effect continues (half-life of hormone ，激素的半衰期，激素的半衰期 ). ).

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

Hormon

e concentration (µg /

L plasma)

Half-lifeHalf-life

HYPOTHALAMUS AND THE HYPOTHALAMUS AND THE PITUITARY GLANDPITUITARY 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 Pituitary gland is located just below the hypothalamus at the base of the brain to which it is connected by a short the base of the brain to which it is connected by a short stalk (named the infundibulumstalk (named the infundibulum ，动脉圆锥，动脉圆锥 ).).

•Pituitary is divided into anterior and posterior portions.Pituitary is divided into anterior and posterior portions.•Secretion of anterior pituitary hormones is under the Secretion of anterior pituitary hormones is under the control of hypothalamic releasing hormones.control of hypothalamic releasing hormones.

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

HYPOTHALAMUS AND THE HYPOTHALAMUS AND THE PITUITARY GLANDPITUITARY 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

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

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

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

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

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

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

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

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

Vasculature

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

Anterior Pituitary HormonesAnterior Pituitary Hormones• Seven hormones are secreted by groups of Seven hormones are secreted by groups of

anterior pituitary cell: TSH, FSH, LH, ACTH, MSH, anterior pituitary cell: TSH, FSH, LH, ACTH, MSH, GH, prolactin.GH, prolactin.

• Trophic action is the primary effect of anterior Trophic action is the primary effect of anterior pituitary hormones.pituitary hormones.

• Anterior pituitary hormones can be organized into Anterior pituitary hormones can be organized into three groups based on chemical and functional three groups based on chemical and functional similarities: similarities: TSH, FSH, LH (same TSH, FSH, LH (same α-chain and different β-α-chain and different β-chainchain)); ; ACTH and MSH (derived from ACTH and MSH (derived from proopiomelanocortin, POMC)proopiomelanocortin, POMC); ; GH and prolactin GH and prolactin (straight amino acid chain, about 75% same)(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.

Growth Hormone (GH)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 growth insulin-like growth factor 1 ( IGF-1factor 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 by consequential increase in blood glucose levels; increased fat metabolism by adipose tissue; and increased tissue amino acid uptake. These metabolic adipose tissue; and increased tissue amino acid uptake. These metabolic effects lead to an increase in lean body mass and to an elevation in blood effects lead to an increase in lean body mass and to an elevation in blood insulin levels. insulin levels.

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

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

• In the nonlactating person, the effect of dopamine dominates In the nonlactating person, the effect of dopamine dominates so blood levels of PRL are low. At puberty in the female, PRL so blood levels of PRL are low. At puberty in the female, PRL enhances the ability of the elevated levels of estrogen and enhances the ability of the elevated levels of estrogen and progesterone to stimulate breast development.progesterone to stimulate 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 production does not occur because the high levels of estrogen and progesterone act on the mammary gland to block the and progesterone act on the mammary gland to block the lactogenic effect of PRL. At birth, the mother’s blood levels of lactogenic effect of PRL. At birth, the mother’s blood levels of PRL, estrogen, and progesterone fall. The act of suckling PRL, estrogen, and progesterone fall. The act of suckling stimulates TRH (or some other factor) and inhibits dopamine stimulates TRH (or some other factor) and inhibits dopamine release producing a surge of PRL secretion, which stimulates release producing a surge of PRL secretion, which stimulates milk production. milk production.

Posterior Pituitary HormonesPosterior Pituitary Hormones• Posterior pituitary secretes two hormones, oxytocin (OXT) Posterior pituitary secretes two hormones, oxytocin (OXT)

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

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

THYROID GLANDTHYROID GLANDGeneral OrganizationGeneral Organization

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

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

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

ANATOMY OFANATOMY OF THYROID GLANDTHYROID GLAND

ANATOMY AND HISTOLOGY OF ANATOMY AND HISTOLOGY OF THYROID GLANDTHYROID GLAND

Synthesis of Thyroid HormoneSynthesis of Thyroid Hormone

• Synthesis includes steps that occur within Synthesis includes steps that occur within the epithelial cells and colloid of the the epithelial cells and colloid of the thyroid gland as well as at the target thyroid gland as well as at the target tissue.tissue.

• Iodine uptake and thyroglobulin synthesis Iodine uptake and thyroglobulin synthesis occur within epithelial cells.occur within epithelial cells.

• Iodination of thyroglobulin and synthesis of Iodination of thyroglobulin and synthesis of TT33 and T and T44 occur within the colloid. occur within the colloid.

• TT33, most active form of the hormone, is , most active form of the hormone, is produced from Tproduced from T44 at the target tissue. at 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 Stimulation of hormone secretion by TSH causes the epithelial cells to engulf small globs of colloid the epithelial cells to engulf small globs of colloid and move them into the cell by endocytosis. and move them into the cell by endocytosis. Within the epithelial cell, MIT, DIT, TWithin the epithelial cell, MIT, DIT, T33, and T, and T44 are are secreted into the blood while MIT and DIT are secreted into the blood while MIT and DIT are broken down to I- and tyrosine molecules for 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 are carried in the blood bound toblood bound to thyroxinebinding globulin thyroxinebinding globulin (TBG(TBG ，， ).). T T33 is more biologically active than T is more biologically active than T44, but , but since Tsince T44 synthesis occurs more rapidly, more T synthesis occurs more rapidly, more T44 than Tthan T33 is secreted. Target tissues contain an is secreted. Target tissues contain an enzyme, enzyme, 5’-iodinase5’-iodinase that converts T4 to T3. that converts T4 to T3.

Releases of Thyroid HormoneReleases of Thyroid Hormone

Releases of Thyroid HormoneReleases of Thyroid Hormone

Control of Thyroid Hormone Control of Thyroid Hormone SecretionSecretion

• 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 pituitary thyrotrophs stimulating TSH release. TSH acts on the

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

and secretion. TSH increase iodide uptake by follicular cells, and secretion. TSH increase iodide uptake by follicular cells,

iodination of thyroglobulin, formation of MIT and DIT, and iodination of thyroglobulin, formation of MIT and DIT, and

endocytosis of colloid. These actions are mediated through G-protein endocytosis of colloid. These actions are mediated through G-protein

coupled membrane TSH receptors on the thyroid gland that coupled membrane TSH receptors on the thyroid gland that

stimulate the formation of cyclic AMP and a cascade of protein stimulate the formation of cyclic AMP and a cascade of protein

phosphorylation steps. With sustained TSH release, a trophic effect phosphorylation steps. With sustained TSH release, a trophic effect

occurs causing thyroid gland enlargement.occurs causing thyroid gland enlargement.

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

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

pituitary thyrotrophs to decrease their number of TRH receptors. pituitary thyrotrophs to decrease their number of TRH receptors.

This makes TRH less effective, decreasing the amount of TSH This makes TRH less effective, decreasing the amount of TSH

released and therefore, the amount of thyroid hormone secreted. released and therefore, the amount of thyroid hormone secreted.

The net effect of this feedback process is to produce a relatively The net effect of this feedback process is to produce a relatively

constant blood level of thyroid hormones. constant blood level of thyroid 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

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

• Thyroid hormones are required for normal growth throughout Thyroid hormones are required for normal growth throughout life.life.

• Thyroid hormones affect basal metabolic rate (BMR, raises Thyroid hormones affect basal metabolic rate (BMR, raises the cellular oxygen consumption and heat production), the cellular oxygen consumption and heat production), metabolism, the cardiovascular system (CO, Ventricular metabolism, the cardiovascular system (CO, Ventricular contractility and HRcontractility 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 autoimmune disease named Graves’ disease or hypothyroidism, also an autoimmune destruction of the hypothyroidism, also an autoimmune destruction of the thyroid gland, thyroiditis , maybe cretinism thyroid gland, thyroiditis , maybe cretinism occur).occur).

HyperthyroidismHyperthyroidism

HypothyroidismHypothyroidism

CretinismCretinism

ADRENAL GLANDADRENAL GLANDGeneral 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

Adrenal CortexAdrenal Cortex

Hormone SynthesisHormone Synthesis

•Hormones of the cortex are all derived Hormones of the cortex are all derived from cholesterol (blood).from cholesterol (blood).

•Each cortical layer possesses unique Each cortical layer possesses unique enzymes (P450 oxidases) that permit enzymes (P450 oxidases) that permit the synthesis of layer-specific the synthesis of layer-specific hormones from the common precursor, hormones from the common precursor, pregnenolone.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 angiotensinⅡand K ions stimulate secretion from the zona glomerulosa.

Control of Adrenal Cortex Control of Adrenal Cortex hormone secretionhormone secretion

• Secretions of the zona fasciculata and reticularis are Secretions of the zona fasciculata and reticularis are under the sole control of the CRH-ACTH axis.under the sole control of the CRH-ACTH axis.

• Cortisol secretion from the zona fasciculata is Cortisol secretion from the zona fasciculata is pulsatile with a diurnal rhythm driven by activity pulsatile with a diurnal rhythm driven by activity within the brain.within the brain.

• Stress stimulates the hypothalamus-pituitary-adrenal Stress stimulates the hypothalamus-pituitary-adrenal axis to increase cortisol secretion.axis to increase cortisol secretion.

• Cortisol secretion is limited by a negative feedback Cortisol secretion is limited by a negative feedback system at the lever of both the hypothalamus and system at the lever of both the hypothalamus and anterior pituitary.anterior pituitary.

• Secretion of the zona glomerulosa are affected Secretion of the zona glomerulosa are affected primarily by the action of angiotensinⅡand to a lesser primarily by the action of angiotensinⅡand to a lesser extent by K ions and ACTH.extent by K ions 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 hypothalamus Cortisol limits its own secretion at the level of the hypothalamus and anterior pituitary.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.

Glucocorticoid ActionGlucocorticoid Action • Glucocorticoids (cortisol) are essential for life, Glucocorticoids (cortisol) are essential for life,

and without it, we cannot survive.and without it, we cannot survive.

• It increases blood glucose levels (especially It increases blood glucose levels (especially

during starvation, hypoglycemia, stress and during starvation, hypoglycemia, stress and

trauma), synthesis in the liver and reduces trauma), synthesis in the liver and reduces

glucose utilization by muscle and fat cells, glucose utilization by muscle and fat cells,

inhibiting insulin effect.inhibiting insulin effect.

• Glucocorticoids are catabolic and diabetogenic, Glucocorticoids are catabolic and diabetogenic,

reduce inflammation (Preduce inflammation (PGG↓, IL-2↓,His↓5-HT↓T-Cell↓↓, IL-2↓,His↓5-HT↓T-Cell↓), ),

suppress immune responses, and support suppress immune responses, and support

vascular response to catecholamines.vascular response to catecholamines.

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

Androgen Action Androgen Action

• Adrenal androgens play an important role Adrenal androgens play an important role

in the female but not in the male Because in the female but not in the male Because

it do not contribute significantly to it do not contribute significantly to

testosterone synthesis.testosterone synthesis.

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

for the development of public and axillary for the development of public and axillary

hair and for libido. hair and for libido.

Pathology ofPathology of Adrenal CortexAdrenal Cortex

• Abnormal adrenocortical secretion can Abnormal adrenocortical secretion can result from alterations in the gland result from alterations in the gland itself, the hypothalamus, or the itself, the hypothalamus, or the anterior pituitary.anterior pituitary.

• Abnormalities of the adrenal cortex Abnormalities of the adrenal cortex include Addison’s disease , Cushing’s include Addison’s disease , Cushing’s syndrome, and Conn’s syndrome.syndrome, and Conn’s syndrome.

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

Adrenal MedullaAdrenal Medulla

• The adrenal medulla is essentially a neuroendocrine The adrenal medulla is essentially a neuroendocrine organ that is activated by sympathetic organ that is activated by sympathetic preganglionic nerves. 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 Catecholamines have widespread effects (through β-adrenergic G-protein linked membrane receptors) β-adrenergic G-protein linked membrane receptors) on the cardiovascular system, muscle system, and on the cardiovascular system, muscle system, and metabolism (blood glucose levelsmetabolism (blood glucose levels↑↑).).

PANCREASPANCREAS

ENDOCRINE PANCREASENDOCRINE PANCREASGeneral OrganizationGeneral Organization

• Cells of the endocrine pancreas are organized into Cells of the endocrine pancreas are organized into clusters called islets of Langerhans.clusters called islets of Langerhans.

• Islets of Langerhans are composed of three cell Islets of Langerhans are composed of three cell typestypes －－ alpha, beta, and delta—that secret alpha, beta, and delta—that secret glucagons, insulin, and somatostatin, glucagons, insulin, and somatostatin, respectively.respectively.

• Blood flow from the beta cells carries insulin past Blood flow from the beta cells carries insulin past the alpha and delta cells and reduces their the alpha and delta cells and reduces their secretion of glucagons and somatostatin, secretion of glucagons and somatostatin, receptively.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.

HISTOLOGY OF PANCREASHISTOLOGY OF PANCREAS

HISTOLOGY OF PANCREASHISTOLOGY OF PANCREAS

InsulinInsulin • Insulin is synthesized by β-cells from a Insulin is synthesized by β-cells from a

prohormone. prohormone.

• Insulin is the hormone of plenty and is released Insulin is the hormone of plenty and is released when metabolic supply (primarily glucose) when metabolic supply (primarily glucose) exceeds the needs of the body. exceeds the needs of the body.

• Operating through tyrosine kinase receptors on Operating through tyrosine kinase receptors on liver, skeletal muscle, and adipose cells, insulin liver, skeletal muscle, and adipose cells, insulin conserves glucose and increases fat storage and conserves glucose and increases fat storage and protein synthesis. protein synthesis.

• Insulin also helps maintain a low blood K ion level Insulin also helps maintain a low blood K ion level by stimulating the Na-K-ATPase pump.by stimulating the Na-K-ATPase pump.

Synthesis of InsulinSynthesis 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.

Secretion of InsulinSecretion 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 concentration. Elevated Ca induces fusion of the storage vesicles with the cell membrane and stimulates insulin release. Fatty acids with the cell membrane and stimulates insulin release. Fatty acids and amino acids also stimulate insulin secretion, presumably and amino acids also stimulate insulin secretion, presumably through a similar mechanism. Glucagon stimulates insulin secretion through a similar mechanism. Glucagon stimulates insulin secretion by acting directly through a G- protein linked receptor on β-cells as by acting directly through a G- protein linked receptor on β-cells as well as indirectly by elevating blood glucose levels (see next well as indirectly by elevating blood glucose levels (see next section). On the other hand, somatostatin inhibits insulin secretion section). On the other hand, somatostatin inhibits insulin secretion by acting directly on the β-cells and indirectly by reducing the ability by acting directly on the β-cells and indirectly by reducing the ability of glucagon to stimulate insulin secretion. of glucagon to stimulate insulin secretion.

Function of InsulinFunction 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

Mechanism of InsulinMechanism of Insulin

Mechanism of InsulinMechanism of Insulin

Mechanism of InsulinMechanism of Insulin

GlucagonGlucagon • Glucagon is a single chain of 29 amino acids Glucagon is a single chain of 29 amino acids

synthesized by α-cells.synthesized by α-cells.• Glucagon acts primarily on the liver to increase and Glucagon acts primarily on the liver to increase and

maintain blood glucose levels.maintain blood glucose levels.• Glucagons secretion is increased in response to falling Glucagons secretion is increased in response to falling

blood glucose and increasing blood amino acid levels.blood glucose and increasing blood amino acid levels.• Glucagon secretion is inhibited by insulin acting Glucagon secretion is inhibited by insulin acting

directly on α-cell through the insulin-receptor.directly on 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 glucose synthesis from amino acids and by stimulating fat metabolism.fat metabolism.

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

Function of GlucagonFunction 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.

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

Somatostatin Somatostatin

• Somatostatin is a peptide hormone Somatostatin is a peptide hormone released from released from δ-δ-cells. cells.

• Somatostatin acts in a paracrine Somatostatin acts in a paracrine manner to inhibit glucagon and manner to inhibit glucagon and insulin secretion locally.insulin secretion locally.

• Somatostatin secretion is increased in Somatostatin secretion is increased in response to a meal and, therefore, response to a meal and, therefore, acts to modulate the response of acts to modulate the response of insulin and glucagon to a meal. insulin and glucagon to a meal.

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

is in two forms. is in two forms.

• Type I is primarily due to the inability of β-cells to produce Type I is primarily due to the inability of β-cells to produce and secrete insulin (autoimmune reaction); type Ⅱ is and secrete insulin (autoimmune reaction); type Ⅱ is characterized by marked resistance of target tissues to characterized by marked resistance of target tissues to insulin (obesity, aging, various illnesses).insulin (obesity, aging, 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 levels, elevated blood amino acid levels, and elevated free fatty acids leading to formation of ketone bodies and fatty acids leading to formation of ketone bodies and acidemia.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 Chronic complications of this metabolic disorder affect the eyes, the kidneys, the peripheral nervous system, and the eyes, the kidneys, the peripheral nervous system, and the vascular system. vascular 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

NeuropeptideNeuropeptide ，，

Structure of BoneStructure of Bone

Histology of BoneHistology of Bone

Histology of BoneHistology of Bone

CALCIUM AND PHOSPHATE CALCIUM AND PHOSPHATE REGULATIONREGULATION

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.

Parathyroid GlandParathyroid Gland

• Parathyroid gland senses blood Ca Parathyroid gland senses blood Ca levels through cell surface receptors. levels through cell surface receptors.

• Parathyroid gland secretes PTH (84 Parathyroid gland secretes PTH (84 amino acids) in response to reduced amino acids) in response to reduced blood Ca levels (by cAmp-induced blood Ca levels (by cAmp-induced mechanism).mechanism).

• PTH stimulates (1) bones dissolution, PTH stimulates (1) bones dissolution, (2) renal Ca reabsorption, and (3) (2) renal Ca reabsorption, and (3) intestinal Ca absorption.intestinal Ca absorption.

Function of Parathyroid HormoneFunction of Parathyroid Hormone

Vitamin DVitamin D• Vitamin D (cholecalciferol) is a steroid obtained Vitamin D (cholecalciferol) is a steroid obtained

from the diet or synthesized by the skin (from from the diet or synthesized by the skin (from cholesterol under the effect of ultraviolet cholesterol under the effect of ultraviolet light).light).

• Active form of vitamin D (1,25 Active form of vitamin D (1,25 dihydroxycholecalciferol) is formed in the dihydroxycholecalciferol) is formed in the kidneys through the action of 1α-hydroxylase.kidneys through the action of 1α-hydroxylase.

• Activity of 1α-hydroxylase is influenced by the Activity of 1α-hydroxylase is influenced by the blood levels of Ca and PTH.blood 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 phosphate (from DNA levels) through actions on the small intestines, kidneys, and bone. on the small intestines, kidneys, and bone.

Function of Vitamin DFunction of Vitamin D

CalcitoninCalcitonin

• Calcitonin (32 amino acids) is Calcitonin (32 amino acids) is synthesized by parafollicular cells or C synthesized by parafollicular cells or C cells of the thyroid gland. cells of the thyroid gland.

• Increased blood Ca levels stimulate Increased blood Ca levels stimulate calcitonin secretion.calcitonin secretion.

• Calcitonin inhibits osteoclast bone Calcitonin inhibits osteoclast bone resorption reducing blood Ca levels.resorption reducing blood Ca levels.

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

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