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

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.

Endocrine System

Regulation of endocrine system

Nerve system

Endocrine system

Immuno system

Historical retrospect

1 、 Gland Endocrinology ( 1850-1950)

2 、 Tissue Endocrinology 1950-

3 、 Molecular Endocrinology

　　

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

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

Endocrine cell Free hormone Carrier-bound hormone

Hormone receptor

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

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

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 system

Hypothalamus Hypophysis Gland Hormone

TRH TSH Thyroid T3/T4

CRH ACTH Adrenal cortisol

GHRH/GIH GH

GnRH FSH/LH Ovarian

Testis

E2 、 AD 、 Testosterone

DA PRL

ADH

OXYTOCIN

Regulation of endocrine system

Hypothalamus

Pituitary

Endocrine glands

Hormone

+

+

+

-

--

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

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

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

Hyperadrenalism – Cushing’s syndrome

Regulation of GH secretion

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

Excessive GH during childhood

Growth plate stimulation

Tumor of somatotrophs

Robert Wardlow 8’ 11”.

Abnormalities of GH secretion

Gigantism

GH late in life Causes excessive growth of flat bones

Acromegaly

Rondo Hatton

Acromegaly

Abnormalities of GH secretion

GH deficiency: nanism

NEUROHYPOPHYSIS

ADH or vasopressin

Supraoptic nucleus

Increased water

reabsorption in kidney

Vasoconstriction in high

dose

DIABETESINSIPIDUS

Endocrine Dysfunction

Thyroid Functionand Disease

Anatomy 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

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)

Regulates thyroid hormone production, secretion, and thyroid growth

Is regulated by the negative feedback action of T4 and T3

Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism

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- and iodination 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

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

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

Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS)

NIS is a membrane protein that mediates active iodide uptake by the thyroid It functions as a I- concentrating mechanism that

enables I- to enter the thyroid for hormone biosynthesis

NIS confers basal cell membranes of thyroid follicular cells with the ability to effect “iodide trapping” by an active transport mechanism

Specialized system assures that adequate dietary I- accumulates in the follicles and becomes available for T4 and T3 biosynthesis

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)

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

Proteolysis of Tg With Release ofT4 and T3

T4 and T3 are synthesized and stored within the Tg

molecule Proteolysis is an essential step for releasing the

hormones To liberate T4 and T3, Tg is resorbed into the follicular cells

in the form of colloid droplets, which fuse with lysosomes to form phagolysosomes

Tg is then hydrolyzed to T4 and T3, which are then secreted into the circulation

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

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

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

SNC: TRß1 e TRß2 + TR1 TR2

Heart: TRß1 e TRß2 + TR1

Liver: TRß1 e TRß2

Kindy: TR1 + TRß1 e TRß2

Hypothalamus- hypophysis: TRß1 e TRß2

Muscle: TR1

Gonad: TR1

Distribution of TH receptors

Biological Role of Thyroid Hormones (THs)

• THs initiate or sustain differentiation and growth, they are essential for childhood growth and for neural development and maturation and function of the CNS

• THs stimulate oxygen consumption by mitochondria, mitochondrial protein synthesis and mitochondrogenesis

THs stimulate Metabolic Activities in 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 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 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

Mediated Thermogenesis

(Peripheral Tissues)

Release Metabolic Endproducts

Local

Vasodilatation

Decreased Systemic Vascular

Resistance

Decreased Diastolic Blood

Pressure

Cardiac Chronotropy and

Inotropy

Increased Cardiac Output

Elevated Blood Volume

T3

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

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

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 (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 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

Hypothyroidism

Hyperthyroidism

Overview of Thyroid Disease States

Euthyroidism Primary Hypothyroidism Primary Hyperthyroidism

hypothalamus

hypophysis

thyroid

hypothalamus

hypophysis

thyroid

hypothalamus

hypophysis

thyroid

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

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

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: 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)

Tiredness

Forgetfulness/Slower Thinking

Moodiness/ Irritability

Depression

Inability to Concentrate

Thinning Hair/Hair Loss

Loss of Body Hair

Dry, Patchy Skin

Weight Gain

Cold Intolerance

Elevated Cholesterol

Family History of Thyroid Disease or

Diabetes

Muscle Weakness/

Cramps

Constipation

Infertility

Menstrual Irregularities/

Heavy Period

Slower Heartbeat

Difficulty Swallowing

Persistent Dry or Sore Throat

Hoarseness/

Deepening of Voice

Enlarged Thyroid (Goiter)

Puffy Eyes

Clinical Features of Hypothyroidism

HYPOTHYROIDISM

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

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

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

Pathogenesis

5-10% of patients without ipertiroidismo50-75% of patients associated with ipertiroidismo,

Graves ophthalmopethy

Graves ophthalmopethy

Graves Disease

T3

Na/K-ATP 酶 UCP metabolism NervesCardiovasculargastro digestion

Producing CalorieReduce body weight

Nervousness/Tremor

Mental Disturbances/ Irritability

Difficulty Sleeping

Bulging Eyes/Unblinking Stare/ Vision

Changes

Enlarged Thyroid (Goiter)

Menstrual Irregularities/

Light Period

Frequent Bowel Movements

Warm, Moist Palms

First-Trimester Miscarriage/

Excessive Vomiting in Pregnancy

Hoarseness/

Deepening of Voice

Persistent Dry or Sore Throat

Difficulty Swallowing

Palpitations/

Tachycardia

Impaired Fertility

Weight Loss or Gain

Heat Intolerance

Increased Sweating

Family History of

Thyroid Disease

or Diabetes

Signs and Symptoms of Hyperthyroidism

Sudden Paralysis

Thyroid dysfunction

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)

Molecular mechanism in papillary thyroid carcinoma

NNRET-PTC

15%15%

40%40%BRAF

RAS

20%20%

PCPC

PCPC

PCPC

FCFC ACAC

Diabetes mellitus

PANCREATIC ISLET

Alpha cells (25%)

Glucagon

Beta cells (60%)

Insulin & amylin

Delta cells (10%)

Somatostatin

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 acts through a tyrosine kinase receptor

FUNCTION OF INSULIN

Insulin being an anabolic hormone stimulates protein & fatty acids synthesis.

Insulin decreases blood sugar 1. By inhibiting hepatic glycogenolysis and

gluconeogenesis.2. By stimulating glucose uptake, utilization &

storage by the liver, muscles & adipose tissue.

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

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.

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

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 -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 differencesFamilial clusteringHigh concordance rate in twinsSpecific genetic markersHigher incidence with genetic syndromes

or chromosomal defects

AUTOIMMUNITY

Circulating antibodies against -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

VirusesCoxaschie BMumpsRubellaReoviruses

Nutrition & dietary factorsCow’s milk proteinContaminated 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

TYPE 2 DIABETES: ETIOLOGY

GENETIC FACTORS

Insulin resistance•Mutation of insulin receptor substance IRS:

IRS-1 mutation Ala 513 Pro 、 Gly 819 Arg 、 Gly 972 Arg、Arg 1221 CysIRS-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

Obesity Assume of high caloric food Stress Age ecc.

ENVIRONMENTAL SUSPECTS

Clinic features of diabetes

principal Polyuria Polydipsia Polyphagia Weight loss in spite of polyphagia

others Hyperglycemia Glucosuria Ketosis Acidosis

COMPLICATIONS OF DIABETES

Acute complicationsDiabetes ketoacidosishypoglycemia

Chronic complicationsRetinopathy NeuropathyNephropathyIschemic heart disease & strokeDiabetic foot ulcersMacrovascular complicationInfection

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

1. Insulin Secretagoguesa ) Sulphonylurea group b) Non Sulphonylurea Insulin Secretagogues

2. Insulin sensitizersa ) Metforminb) Thiazolidinedione

3. Digestive enzyme inhibitor-Glucosidase inhibitor ： Acarbose

Insulin