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Basic Mechanism of Endocrine Disorders. Qi Hongyan. Content. Describe the endocrine system and the process of negative feedback in regulation of hormones production and secretion. Discuss the pathogenesis of hyperthyroidism, hypothyroidism and diabetes mellitus. Endocrine System.

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content
Content

Describe the endocrine system and the process of negative feedback in regulation of hormones production and secretion.

Discuss the pathogenesis of hyperthyroidism, hypothyroidism and diabetes mellitus.

slide3

Endocrine System

Endocrine system uses chemical substances called Hormone as a means of regulating and integrating body functions. It participates in the regulation of digestion, use, and storage of nutrients; growth and development; electrolyte and water metabolism; and reproductive functions.

regulation of endocrine system
Regulation of endocrine system

Nerve system

Immuno system

Endocrine

system

historical retrospect
Historical retrospect

1、Gland Endocrinology( 1850-1950)

2、Tissue Endocrinology1950-

3、Molecular Endocrinology

hormones
Hormones

Hormones generally are thought of as chmical messengers that are transported in body fluids. They are highly specialized organic molecules produced by endocrine organs that exert their action on specific target cells.

classifications of hormones
Classifications of Hormones

Steroid hormones : estrogen, androstenedione, testosterone…

Peptides or proteins : PTH, insulin, oxytocin, GH, FSH, ACTH…

Amine and amino acids derivatives: TH, dopanime…

slide9

Relationship of free and carrier-bound hormones

Carrier-bound

hormone

Free hormone

Endocrine cell

Hormone

receptor

Biological effects

slide10

Activation mechanism of Hormones

Carol mattson porth Pathophysiology 7th edition

slide11

Activation mechanism of Hormones

Carol mattson porth Pathophysiology 7th edition

hypothalamus and hypophysis
Hypothalamus and hypophysis
  • Thyrotropin releasing hormone (TRH)
  • Corticotropin releasing hormone (CRH)
  • Growth hormone releasing hormone (GHRH)
  • Somatostatin as inhibiting hormone (e.g. GH)
  • Gonadotropin releasing hormone (GnRH)
slide13
Pituitary gland (Hypophysis)

Anterior lobe (Adenohypophysis)

Glandular cells (originate from Rathke’s pouch)

Secretes six important peptide hormones

Posterior lobe (Neurohypophysis)

Glial-type cells (neural origin)

Secretes two important peptide hormones

Hypothalamus and hypophysis

hormones of hypophysis
Hormones of hypophysis

Adenohypophysis

Somatotropes – human growth hormone (hGH)

Corticotropes – adrenocorticotropin (ACTH)

Thyrotropes – Thyroid stimulating hormone (TSH)

Gonadotropes – gonadotropic hormones

Luteinizing hormone (LH)

Follicle stimulating hormone (FSH)

Lactotropes– prolactin (PRL)

Neurohypophysis

Antidiuretic hormone(ADH)

oxytocin

regulation of endocrine system1
Regulation of endocrine system

-

-

Hypothalamus

+

-

Pituitary

+

Endocrine

glands

+

Hormone

slide18

Endocrine Dysfunction

  • Hypofunction: defects of gland, defects of enzyme for the hormone synthesis, inflammation, neoplastic growth, defects of receptor…
  • Hyperfunction: excessive hormone production
  • Primary:defects of target gland responsible for producing the hormone
  • Secondary:alteration of regulation for producing the hormone
  • Tertiary:hypotalamic dysfunction
regulation of cortisol secretion
Regulation of cortisol secretion

Hypothalamus (CRH) regulates the secretion of ACTH secretion, which increases in stress

ACTH acts through the second messenger cAMP

It controls the rate limiting step of converting cholesterol to pregnenolone

Circadian rhythm – more in early morning & low in midnight

hyperadrenalism cushing s syndrome
Hyperadrenalism – Cushing’s syndrome

Mobilization of fat from lower parts of body & extra deposition in upper portions – buffalo torso

Moon face

Striae – due to tearing of subcutaneous tissue, by diminished collagen fibers

Increased blood glucose level

Muscle weakness

Loss of protein synthesis in lymphoid tissue suppresses immune system

regulation of gh secretion
Regulation of GH secretion

Carol mattson porth Pathophysiology 7th edition

growth hormone
Growth hormone

Control of GH

Stress, exercise nutrition, sleep

Somatostatin (SS) inhibits

GH causes inhibition of glucose uptake and utilization, increased a.a. uptake and protein synthesis

gigantism
Gigantism

Excessive GH during childhood

Growth plate stimulation

Tumor of somatotrophs

Robert Wardlow 8’ 11”.

slide26
GH late in life

Causes excessive growth of flat bones

Acromegaly

Rondo Hatton

neurohypophysis
NEUROHYPOPHYSIS

ADH or vasopressin

Supraoptic nucleus

Increased water reabsorption in kidney

Vasoconstriction in high dose

follicles the functional units of the thyroid gland
Follicles: the Functional Units of the Thyroid Gland
  • Follicles Are the Sites Where Key Thyroid Elements Function:
  • Thyroglobulin (Tg)
  • Tyrosine
  • Iodine
  • Thyroxine (T4)
  • Triiodotyrosine (T3)
the thyroid produces and secretes 2 metabolic hormones
The Thyroid Produces and Secretes 2 Metabolic Hormones

Two principal hormones

Thyroxine (T4 ) and triiodothyronine (T3)

Required for homeostasis of all cells

Influence cell differentiation, growth, and metabolism

Considered the major metabolic hormones because they target virtually every tissue

thyroid stimulating hormone tsh
Thyroid-Stimulating Hormone (TSH)

Regulates thyroid hormone production, secretion, and thyroid growth

Is regulated by the negative feedback action of T4 and T3

biosynthesis of t 4 and t 3
Biosynthesis of T4 and T3

The process includes

Dietary iodine (I) ingestion

Active transport and uptake of iodide (I-) by thyroid gland

Oxidation of I- andiodination of thyroglobulin (Tg) tyrosine residues

Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3

Proteolysis of Tg with release of T4 and T3 into the circulation

iodine sources
Iodine Sources

Available through certain foods (eg, seafood), iodized salt, or dietary supplements, as a trace mineral

The recommended minimum intake is 150 g/day

active transport and i uptake by the thyroid
Active Transport and I- Uptake by the Thyroid

Dietary iodine reaches the circulation as iodide anion (I-)

The thyroid gland transports I- to the sites of hormone synthesis

I- accumulation in the thyroid is an active transport process that is stimulated by TSH

oxidation of i and iodination of thyroglobulin tg tyrosyl residues
Oxidation of I- and Iodination of Thyroglobulin (Tg) Tyrosyl Residues

I- must be oxidized to be able to iodinate tyrosyl residues of Tg

Iodination of the tyrosyl residues then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are then coupled to form either T3 or T4

Both reactions are catalyzed by TPO

thyroperoxidase tpo
Thyroperoxidase (TPO)

TPO catalyzes the oxidation steps involved in I- activation, iodination of Tg tyrosyl residues, and coupling of iodotyrosyl residues

TPO has binding sites for I- and tyrosine

TPO uses H2O2 as the oxidant to activate I- to hypoiodate (OI-), the iodinating species

t 4 a prohormone for t 3
T4: A Prohormone for T3

T4 is biologically inactive in target tissues until converted to T3

Activation occurs with 5\' deiodination of the outer ring of T4

T3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects

carriers for circulating thyroid hormones
Carriers for Circulating Thyroid Hormones

More than 99% of circulating T4 and T3 is bound to plasma carrier proteins

Thyroxine-binding globulin (TBG), binds about 75%

Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA), binds about 10%-15%

Albumin binds about 7%

High-density lipoproteins (HDL), binds about 3%

Carrier proteins can be affected by physiologic changes, drugs, and disease

free hormone concept
Free Hormone Concept

Only unbound (free) hormone has metabolic activity and physiologic effects

Free hormone is a percentage of total hormone in plasma (about 0.03% T4; 0.3% T3)

Total hormone concentration

Normally is kept proportional to the concentration of carrier proteins

Is kept appropriate to maintain a constant free hormone level

slide43

TR ch 17

TR ch 3

slide44

Distribution of TH receptors

SNC: TRß1 e TRß2 + TR1TR2

Hypothalamus- hypophysis: TRß1 e TRß2

Heart: TRß1 e TRß2 + TR1

Liver: TRß1 e TRß2

Kindy: TR1 + TRß1 e TRß2

Gonad: TR1

Muscle: TR1

biological role of thyroid hormones ths
Biological Role of Thyroid Hormones (THs)
    • THs initiate or sustain differentiation and growth, they are essential for childhood growth and for neural developmentand maturation and function of the CNS
    • THs stimulate oxygen consumptionby mitochondria, mitochondrial protein synthesis and mitochondrogenesis
  • THs stimulate Metabolic Activitiesin Most Tissues exerting calorigenic effetcs, stimulate lypolisis and metabolism of cholesterol
  • THs Influences Cardiovascular Hemodynamics
  • THs influence the Female Reproductive System
thyroid hormone plays a major role in growth and development
Thyroid Hormone Plays a Major Role in Growth and Development

Thyroid hormone initiates or sustains differentiation and growth

Stimulates formation of proteins, which exert trophic effects on tissues

Is essential for normal brain development

Essential for childhood growth

Untreated congenital hypothyroidism or chronic hypothyroidism during childhood can result in incomplete development and mental retardation

thyroid hormones and the central nervous system cns
Thyroid Hormones and the Central Nervous System (CNS)

Thyroid hormones are essential for neural development and maturation and function of the CNS

Decreased thyroid hormone concentrations may lead to alterations in cognitive function

Patients with hypothyroidism may develop impairment of attention, slowed motor function, and poor memory

Thyroid-replacement therapy may improve cognitive function when hypothyroidism is present

thyroid hormone influences cardiovascular hemodynamics
Thyroid Hormone Influences Cardiovascular Hemodynamics

Thyroid hormone

Mediated Thermogenesis

(Peripheral Tissues)

Local

Vasodilatation

Release Metabolic Endproducts

Decreased Systemic Vascular Resistance

T3

Elevated Blood Volume

Cardiac Chronotropy and Inotropy

Decreased Diastolic Blood Pressure

Increased Cardiac Output

Laragh JH, et al. Endocrine Mechanisms in Hypertension. Vol. 2. New York, NY: Raven Press;1989.

thyroid hormone influences the female reproductive system
Thyroid Hormone Influences the Female Reproductive System

Normal thyroid hormone function is important for reproductive function

Hypothyroidism may be associated with menstrual disorders, infertility, risk of miscarriage, and other complications of pregnancy

Doufas AG, et al. Ann N Y Acad Sci. 2000;900:65-76.

Glinoer D. Trends Endocrinol Metab. 1998; 9:403-411.

Glinoer D. Endocr Rev. 1997;18:404-433.

thyroid hormone is critical for normal bone growth and development
Thyroid Hormone is Critical for Normal Bone Growth and Development

T3 is an important regulator of skeletal maturation at the growth plate

T3 regulates the expression of factors and other contributors to linear growth directly in the growth plate

T3 also may participate in osteoblast differentiation and proliferation, and chondrocyte maturation leading to bone ossification

thyroid hormones stimulate metabolic activities in most tissues
Thyroid Hormones Stimulate Metabolic Activities in Most Tissues

Thyroid hormones (specifically T3) regulate rate of overall body metabolism

T3 increases basal metabolic rate

Calorigenic effects

T3 increases oxygen consumption by most peripheral tissues

Increases body heat production

metabolic effects of t 3
Metabolic Effects of T3

Stimulates lipolysis and release of free fatty acids and glycerol

Stimulates metabolism of cholesterol to bile acids

Facilitates rapid removal of LDL from plasma

Generally stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation

overview of thyroid disease states
Overview of Thyroid Disease States

Hypothyroidism

Hyperthyroidism

overview of thyroid disease states1
Overview of Thyroid Disease States

hypothalamus

hypothalamus

hypothalamus

hypophysis

hypophysis

hypophysis

thyroid

thyroid

thyroid

Euthyroidism Primary Hypothyroidism Primary Hyperthyroidism

hypothyroidism
Hypothyroidism
  • Hypothyroidism is a disorder with multiple causes in which the thyroid fails to secrete an adequate amount of thyroid hormone
    • The most common thyroid disorder
    • Usually caused by primary thyroid gland failure
    • Also may result from diminished stimulation of the thyroid gland by TSH
hypothyroidism types
Hypothyroidism: Types
  • Bravernan LE, Utiger RE, eds. Werner & Ingbar\'s The Thyroid. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.
  • Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.
  • Primary hypothyroidism
    • From thyroid destruction
  • Central or secondary hypothyroidism
    • From deficient TSH secretion, generally due to sellar lesions such as pituitary tumor or craniopharyngioma
    • Infrequently is congenital
  • Central or tertiary hypothyroidism
    • From deficient TSH stimulation above level of pituitary—ie, lesions of pituitary stalk or hypothalamus
    • Is much less common than secondary hypothyroidism
primary hypothyroidism underlying causes
Primary Hypothyroidism: Underlying Causes
  • Congenital hypothyroidism
    • Agenesis of thyroid
    • Defective thyroid hormone biosynthesis due to enzymatic defect
  • Thyroid tissue destruction as a result of
    • Chronic autoimmune (Hashimoto) thyroiditis
    • Radiation (usually radioactive iodine treatment for thyrotoxicosis)
    • Thyroidectomy
    • Other infiltrative diseases of thyroid (eg, hemochromatosis)
  • Drugs with antithyroid actions (eg, lithium, radiographic contrast agents, interferon alpha)
hyperthyroidism
Hyperthyroidism

Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues

hyperthyroidism underlying causes
Hyperthyroidism Underlying Causes
  • Signs and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone
    • Toxic diffuse goiter (Graves disease)
    • Toxic uninodular or multinodular goiter
    • Painful subacute thyroiditis
    • Silent thyroiditis
    • Toxic adenoma
    • Iodine and iodine-containing drugs and radiographic contrast agents
    • Trophoblastic disease, including hydatidiform mole
    • Exogenous thyroid hormone ingestion
graves disease
Graves Disease
  • The most common cause of hyperthyroidism
    • Accounts for 60% to 90% of cases
    • Affects more females than males, especially in the reproductive age range
  • Graves disease is an autoimmune disorder possibly related to a defect in immune tolerance
slide64

Graves ophthalmopethy

  • 5-10% of patients without ipertiroidismo
  • 50-75% of patients associated with ipertiroidismo,
slide67

Graves Disease

T3

Nerves

Cardiovascular

gastro digestion

Na/K-ATP酶

UCP

metabolism

Producing Calorie

Reduce body weight

thyroid carcinoma
Thyroid Carcinoma

Incidence

Thyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid disease

Thyroid cancers account for only 1% of cancers

The annual rate has increased nearly 11 new cases/year/100000

Mortality is 0,4-0,8/100000 inn men and women, respectively

Thyroid carcinomas

Papillary (80%)

Follicular (about 10%)

Medullary thyroid (5%-10%)

Anaplastic carcinoma (1%-2%)

Primary thyroid lymphomas (rare)

Metastatic from other primary sites (rare)

slide70

FC

AC

N

Molecular mechanism in papillary thyroid carcinoma

BRAF

PC

40%

RAS

PC

15%

RET-PTC

PC

20%

pancreatic islet
PANCREATIC ISLET

Alpha cells (25%)

Glucagon

Beta cells (60%)

Insulin & amylin

Delta cells (10%)

Somatostatin

control of insulin secretion
Control of insulin secretion

Increased blood glucose stimulates insulin secretion

Some amino acids (arginine & lysine) when present along with ↑ glucose stimulates insulin secretion

Hormones like glucagon, GH, cortisol etc act directly or indirectly to ↑ insulin secretion

insulin and glucagon
Insulin and glucagon

Carol mattson porth Pathophysiology 7th edition

function of insulin
FUNCTION OF INSULIN
  • Insulin being an anabolic hormone stimulates protein & fatty acids synthesis.
  • Insulin decreases blood sugar
    • By inhibiting hepatic glycogenolysis and gluconeogenesis.
    • By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue.
metabolic effects of insulin
Metabolic effects of Insulin

Effect of insulin on carbohydrate metabolism

Insulin promotes glucose uptake & metabolism in muscle cells, adipose tissues etc. by translocating the GLUT

Insulin promotes glucose uptake & storage in liver

Insulin inactivates liver phosphorylase which prevents glycogen break down

It ↑ activity of glucokinase, causing the phosphorylation of glucose & then glucose get trapped inside

It ↑ activity of enzymes for glycogen synthesis (glycogen synthase)

Insulin promotes conversion of excess glucose into fatty acids & inhibits gluconeogenesis in liver

The brain cells are permeable to glucose & can use glucose without the intermediation of insulin

effect of insulin on fat metabolism
Effect of insulin on fat metabolism

Since insulin ↑ utilization of glucose by most cells, causes ↓ utilization of fat, leading to fat storage

In liver cells excess glycogen prevents the further formation of glycogen & the glucose thus entering gets converted to pyruvate by glycolysis & forms the acetyl CoA which leads to the formation of fatty acids

On adipose tissue insulin inhibits the action of lipases, preventing the hydrolysis of fats

Glucose entered into adipose tissue gets converted to α–glycerol phosphate, which helps in the formation of triglycerides & thus the storage of fat.

effect of insulin on protein metabolism growth
Insulin promotes protein synthesis & storage.

It inhibits the catabolism of proteins

Insulin stimulates transport of many of the amino acids (especially valine, leucine, isoleucine, tyrosine, & phenylalanine) into the cells

Insulin & growth hormone interact synergistically to promote growth – GH also cause the uptake of amino acids, but a different selection as from that of insulin

Effect of insulin on protein metabolism & growth
definition
DEFINITION

The term diabetes mellitus describes a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.

diabetes epidemiology
DIABETES EPIDEMIOLOGY

Diabetes is the most common endocrine problem & is a major health hazard worldwide.

Incidence of diabetes is alarmingly increasing all over the globe.

5% of the general population are diagnosed with diabetes.

who classification 2000
WHO CLASSIFICATION 2000
  • Is based on etiology not on type of treatment or age of the patient.
  • Type 1 Diabetes

(idiopathic or autoimmune b-cell destruction)

  • Type 2 Diabetes

(defects in insulin secretion or action)

  • Other specific types
  • Gestational diabetes
type 1 diabetes etiology
TYPE 1 DIABETES: ETIOLOGY

Type 1 diabetes mellitus is an autoimmune disease.

It is triggered by environmental factors in genetically susceptible individuals.

Both humoral & cell-mediated immunity are stimulated.

genetic factors
GENETIC FACTORS
  • Evidence of genetics is shown in
  • Ethnic differences
  • Familial clustering
  • High concordance rate in twins
  • Specific genetic markers
  • Higher incidence with genetic syndromes or chromosomal defects
autoimmunity
AUTOIMMUNITY

Circulating antibodies against b-cells and insulin.

ICA islet cell autoantibody

IAA autoantibody to insulin

GADA autoantibody to glutamic acid decarboxylase

IA-2 autoantibody to tyrosine phosphatases IA-2

environmental suspects
ENVIRONMENTAL SUSPECTS
  • Viruses
    • Coxaschie B
    • Mumps
    • Rubella
    • Reoviruses
  • Nutrition & dietary factors
    • Cow’s milk protein
    • Contaminated sea food

Chemistry compounds or drugs

slide87

TYPE 2 DIABETES: ETIOLOGY

Interaction of genetic and environmental factors that impair insulin secretion and produce insulin resistance

Impaired glucose uptake by skeletal muscle

Increased in hepatic gluconeogenesis

genetic factors1
GENETIC FACTORS

Insulin resistance

  • Mutation of insulin receptor substance IRS:
  • IRS-1 mutation Ala 513 Pro、Gly 819 Arg 、Gly 972 Arg、 Arg 1221 Cys
  • IRS-2 mutation Gly 1057 Asp
  • Mutation of Glucose transporter GLUT4
  • Mutation of Insulin receptor
  • Mutation of uncoupling protein UCP

B cell defects

  • Mutation of glucokinase GCK
  • Mutation of GLUT2
  • Defects of mitochondrion
  • Defects of insulin synthesis
  • Mutant insulin
  • Abnormal amylin secretion
environmental suspects1
ENVIRONMENTAL SUSPECTS
  • Obesity
  • Assume of high caloric food
  • Stress
  • Age ecc.
clinic features of diabetes
Clinic features of diabetes

principal

Polyuria

Polydipsia

Polyphagia

Weight loss in spite of polyphagia

others

Hyperglycemia

Glucosuria

Ketosis

Acidosis

complications of diabetes
COMPLICATIONS OF DIABETES

Acute complications

Diabetes ketoacidosis

hypoglycemia

  • Chronic complications
    • Retinopathy
    • Neuropathy
    • Nephropathy
    • Ischemic heart disease & stroke
    • Diabetic foot ulcers
    • Macrovascular complication
    • Infection
diet regulation
DIET REGULATION

Regular meal plans with calorie exchange options are encouraged.

50-60% of required energy to be obtained from complex carbohydrates.

Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars.

Encouraged low salt, low saturated fats and high fiber diet.

antidiabetic agents
Antidiabetic Agents

1. Insulin Secretagogues

a ) Sulphonylurea group

b) Non Sulphonylurea Insulin Secretagogues

2. Insulin sensitizers

a ) Metformin

b) Thiazolidinedione

3. Digestive enzyme inhibitor

-Glucosidase inhibitor: Acarbose

Insulin

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