Download Thyroid stimulating hormone

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
Immuno system
Endocrine
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
Hormone
receptor
Biological effects
Carrier-bound
hormone
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)
Hypothalamus and hypophysis
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
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
TRH
TSH
Gland
Thyroid
Hormone
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
Robert Wardlow 8’ 11”.
Gigantism
 Excessive GH during
childhood
 Growth plate stimulation
 Tumor of somatotrophs
Abnormalities of GH secretion
 Gigantism
Acromegaly
 GH late in life
 Causes excessive growth of flat bones
Rondo Hatton
Abnormalities of GH secretion
 Acromegaly
GH deficiency: nanism
NEUROHYPOPHYSIS
ADH or vasopressin
 Supraoptic nucleus
 Increased water
reabsorption in kidney
 Vasoconstriction in high
dose
DIABETES
INSIPIDUS
Endocrine Dysfunction
Thyroid Function
and 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 Axis
Negative 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 of
T4 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
Distribution of TH receptors
SNC: TRß1 e TRß2 + TR1
TR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)
• 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
T3
Elevated Blood
Volume
Increased
Cardiac Output
Cardiac
Chronotropy and
Inotropy
Local
Vasodilatation
Decreased
Systemic
Vascular
Resistance
Decreased
Diastolic Blood
Pressure
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
hypothalamus
hypothalamus
hypophysis
hypophysis
hypophysis
thyroid
thyroid
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)
Clinical Features of Hypothyroidism
Tiredness
Puffy Eyes
Forgetfulness/Slower Thinking
Enlarged Thyroid (Goiter)
Moodiness/ Irritability
Hoarseness/
Deepening of Voice
Depression
Inability to Concentrate
Persistent Dry or Sore Throat
Thinning Hair/Hair Loss
Difficulty Swallowing
Loss of Body Hair
Slower Heartbeat
Dry, Patchy Skin
Menstrual Irregularities/
Heavy Period
Weight Gain
Cold Intolerance
Infertility
Elevated Cholesterol
Constipation
Family History of Thyroid
Disease or Diabetes
Muscle Weakness/
Cramps
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
Graves ophthalmopethy
5-10% of patients without ipertiroidismo
50-75% of patients associated with ipertiroidismo,
Graves ophthalmopethy
Graves Disease
T3
Na/K-ATP酶
UCP
Producing Calorie
Reduce body weight
metabolism
Nerves
Cardiovascular
gastro digestion
Signs and Symptoms of Hyperthyroidism
Nervousness/Tremor
Mental Disturbances/
Irritability
Hoarseness/
Deepening of Voice
Persistent Dry or Sore Throat
Difficulty Swallowing
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/
Vision Changes
Enlarged Thyroid (Goiter)
Menstrual Irregularities/
Light Period
Palpitations/
Tachycardia
Impaired Fertility
Weight Loss or Gain
Heat Intolerance
Increased Sweating
Frequent Bowel Movements
Warm, Moist Palms
First-Trimester Miscarriage/
Excessive Vomiting in Pregnancy
Sudden Paralysis
Family History of
Thyroid Disease
or Diabetes
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
PC
40%
N
15%
FC
PC
PC
20%
AC
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.
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
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 differences
 Familial clustering
 High concordance rate in twins
 Specific genetic markers
 Higher 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
 Viruses
 Coxaschie B
 Mumps
 Rubella
 Reoviruses
 Nutrition & dietary factors
 Cow’s milk protein
 Contaminated sea food
Chemistry compounds or drugs
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 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 SUSPECTS




Obesity
Assume of high caloric food
Stress
Age ecc.
Clinic features of diabetes
principal




Polyuria
Polydipsia
Polyphagia
Weight loss in spite of polyphagia
others




Hyperglycemia
Glucosuria
Ketosis
Acidosis
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
 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 Secretagogues
a ) Sulphonylurea group
b) Non Sulphonylurea Insulin Secretagogues
2. Insulin sensitizers
a ) Metformin
b) Thiazolidinedione
3. Digestive enzyme inhibitor
-Glucosidase inhibitor
Insulin
： Acarbose