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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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 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.
1、Gland Endocrinology( 1850-1950)
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.
Steroid hormones : estrogen, androstenedione, testosterone…
Peptides or proteins : PTH, insulin, oxytocin, GH, FSH, ACTH…
Amine and amino acids derivatives: TH, dopanime…
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
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)
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
Mobilization of fat from lower parts of body & extra deposition in upper portions – buffalo torso
Striae – due to tearing of subcutaneous tissue, by diminished collagen fibers
Increased blood glucose level
Loss of protein synthesis in lymphoid tissue suppresses immune system
Carol mattson porth Pathophysiology 7th edition
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”.
Causes excessive growth of flat bones
ADH or vasopressin
Increased water reabsorption in kidney
Vasoconstriction in high dose
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
Regulates thyroid hormone production, secretion, and thyroid growth
Is regulated by the negative feedback action 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
Available through certain foods (eg, seafood), iodized salt, or dietary supplements, as a trace mineral
The recommended minimum intake is 150 g/day
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
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
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
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
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
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 3
SNC: TRß1 e TRß2 + TR1TR2
Hypothalamus- hypophysis: TRß1 e TRß2
Heart: TRß1 e TRß2 + TR1
Liver: TRß1 e TRß2
Kindy: TR1 + TRß1 e TRß2
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 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
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.
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.
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 (specifically T3) regulate rate of overall body metabolism
T3 increases basal metabolic rate
T3 increases oxygen consumption by most peripheral tissues
Increases body heat production
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
Euthyroidism Primary Hypothyroidism Primary Hyperthyroidism
Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues
Reduce body weight
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
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
Alpha cells (25%)
Beta cells (60%)
Insulin & amylin
Delta cells (10%)
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
Carol mattson porth Pathophysiology 7th edition
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
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.
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 insulinEffect of insulin on protein metabolism & growth
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 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.
(idiopathic or autoimmune b-cell destruction)
(defects in insulin secretion or action)
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.
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
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
B cell defects
Weight loss in spite of polyphagia
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.
1. Insulin Secretagogues
a ) Sulphonylurea group
b) Non Sulphonylurea Insulin Secretagogues
2. Insulin sensitizers
a ) Metformin
3. Digestive enzyme inhibitor
-Glucosidase inhibitor： Acarbose