Basic Mechanism of Endocrine Disorders
1 / 96

Basic Mechanism of Endocrine Disorders - PowerPoint PPT Presentation

  • Uploaded on

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.

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about ' Basic Mechanism of Endocrine Disorders' - carson-glass

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript


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

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



Historical retrospect
Historical retrospect

1、Gland Endocrinology( 1850-1950)

2、Tissue Endocrinology1950-

3、Molecular Endocrinology


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…

Relationship of free and carrier-bound hormones



Free hormone

Endocrine cell



Biological effects

Activation mechanism of Hormones

Carol mattson porth Pathophysiology 7th edition

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)

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


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)


Antidiuretic hormone(ADH)


Regulation of endocrine system1
Regulation of endocrine system












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


Excessive GH during childhood

Growth plate stimulation

Tumor of somatotrophs

Robert Wardlow 8’ 11”.

GH late in life

Causes excessive growth of flat bones


Rondo Hatton

Abnormalities of gh secretion1


Abnormalities of GH secretion


ADH or vasopressin

Supraoptic nucleus

Increased water reabsorption in kidney

Vasoconstriction in high dose

Thyroid function and disease

Thyroid Functionand Disease

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

TR ch 17

TR ch 3

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)



    Release Metabolic Endproducts

    Decreased Systemic Vascular Resistance


    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 T Tissues3

    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 Tissues



    Overview of thyroid disease states1
    Overview of Thyroid Disease States Tissues










    Euthyroidism Primary Hypothyroidism Primary Hyperthyroidism

    Hypothyroidism Tissues

    • 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 Tissues

    • 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 Tissues

    • 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 Tissues

    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 Tissues

    • 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 Tissues

    • 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

    Graves ophthalmopethy Tissues

    • 5-10% of patients without ipertiroidismo

    • 50-75% of patients associated with ipertiroidismo,

    Graves Disease Tissues




    gastro digestion




    Producing Calorie

    Reduce body weight

    Thyroid carcinoma
    Thyroid Carcinoma Tissues


    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)

    FC Tissues



    Molecular mechanism in papillary thyroid carcinoma










    Pancreatic islet

    Alpha cells (25%)


    Beta cells (60%)

    Insulin & amylin

    Delta cells (10%)


    Control of insulin secretion
    Control of insulin secretion Tissues

    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 Tissues

    Carol mattson porth Pathophysiology 7th edition

    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 Tissues

    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 Tissues

    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. Tissues

    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 Tissues

    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 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

    • 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 mellitus is an autoimmune disease.

    It is triggered by environmental factors in genetically susceptible individuals.

    Both humoral & cell-mediated immunity are stimulated.

    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


    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

    • Viruses

      • Coxaschie B

      • Mumps

      • Rubella

      • Reoviruses

    • Nutrition & dietary factors

      • Cow’s milk protein

      • Contaminated sea food

        Chemistry compounds or drugs


    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

    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

    • Obesity

    • Assume of high caloric food

    • Stress

    • Age ecc.

    Clinic features of diabetes
    Clinic features of diabetes Tissues





    Weight loss in spite of polyphagia






    Complications of diabetes

    Acute complications

    Diabetes ketoacidosis


    • Chronic complications

      • Retinopathy

      • Neuropathy

      • Nephropathy

      • Ischemic heart disease & stroke

      • Diabetic foot ulcers

      • Macrovascular complication

      • Infection

    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 Tissues

    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