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.
Regulation of endocrine system Nerve system Immuno system Endocrine system
Historical retrospect 1、Gland Endocrinology( 1850-1950) 2、Tissue Endocrinology1950- 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 Carrier-bound hormone Free hormone Endocrine cell 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 + - 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
Regulation of GH secretion Carol mattson porth Pathophysiology 7th edition
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
NEUROHYPOPHYSIS ADH or vasopressin Supraoptic nucleus Increased water reabsorption in kidney Vasoconstriction in high dose
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
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 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
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
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 + TR1TR2 Hypothalamus- hypophysis: TRß1 e TRß2 Heart: TRß1 e TRß2 + TR1 Liver: TRß1 e TRß2 Kindy: TR1 + TRß1 e TRß2 Gonad: TR1 Muscle: TR1
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 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) 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 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