The Endocrine System Part 2

The Endocrine System Part B

Thyroid Gland  Location:  Located in the anterior neck, in front of trachea  Shape ,Size & weight:  H or Butterfly shaped,Consisting of two lateral lobes connected by a median tissue mass called the isthmus  The largest pure endocrine gland, 12-15mm in Height  Weight 15-20g  Histology  Internally, the gland is composed of hollow, spherical follicles or Acini (50-500µm in diameter)  The follicle walls are formed by cuboidal or

Thyroid Gland

 Lumen of the follicle stores colloid, consisting of thyroglobulin + iodine  Thyroid hormone is derived from this iodinated thyroglobulin  T4 (93%) and T3 (7%)  When the gland is inactive, the colloid is abundant, the follicles are large, and the cells lining them are flat.  When the gland is active, the follicles are small, the cells are cuboid or columnar  The parafollicular cells (C-cells)  Don’t reach the lumen  Lie in the follicular epithelium and protrude

Thyroid Gland Anatomy

Thyroid Gland

Thyroid Hormone

 Thyroid hormone – the body’s major metabolic hormone  Consists of two closely related iodinecontaining compounds  T4 – thyroxine; has two tyrosine molecules plus four bound iodine atoms  T3 – triiodothyronine; has two tyrosines with three bound iodine atoms

T3 and T4 Structures

T 4 or Thyroxine

T 3 or Triiodothyronine

Synthesis of Thyroid Hormone  Each step in the synthesis is stimulated by TSH.  Formation and storage of thyroglobulin  Ribosomes Thyroglobin  Glogi  Glycated & paceked in vesicles  discharged in follicle lumen

 Iodide trapping: (Na+/I- symporter) (30 times more conc.)





 Iodides (I–) are actively taken into the cell, oxidized to iodine (I2) (thyroid perxodiase, TPO), and released into the lumen. (TSH uptake 250 times), (ClO-4, SCNInhibit uptake) Organification: Iodine attaches to tyrosine, (20 tyrosine residues) mediated by TPO enzymes, forming T1 (monoiodotyrosine, or MIT), and T2 (diiodotyrosine, or DIT) (Stimulated by TSH, Inhibited by Thiouracil) Coupling: Iodinated tyrosines link together to form T3

Synthesis of Thyroid Hormone

Synthesis of Thyroid Hormone

Transport and Regulation of TH

 T4 and T3 bind to thyroxine-binding globulins (TBGs) produced by the liver  Both bind to target receptors, but T3 is ten times more active than T4  Peripheral tissues convert T4 to T3 enzymetically  Mechanisms of activity are similar to steroids  Regulation is by negative feedback  Hypothalamic thyrotropin-releasing hormone (TRH) can overcome the negative feedback in high energy

Effects of Thyroid Hormone  Calorigenic Action  Increase oxygen consumption of all metabolically active tissues, Increases BMR  The exceptions are the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary  Carbohydrate Metabolism  Increases absorption of glucose from GIT  Increases utilization of glucose  Increases insulin secretion  Increases glycolysis in liver  Protein Metabolism  Increases protein synthesis by increasing translation and transcritption  Normal amounts anabolic effects

Effects of Thyroid Hormone

 Fat Metabolism  Mobilizes Fatty acids from Fat source  Increases circulating FFA levels  Accelerates FFA oxidation  Hypersecretions decrease the conc. of Cholesterol, triglycerides and phospholipids in plasma  Water and Mineral metabolism  Promotes demineralization of bones  Increases excretion of Calcium and phosphate in urine  Causes diuresis  Vitamins Metabolism  Increased demands of Vitamins as they are

Effects of Thyroid Hormone

 Effects on CVS  Increased blood flow to skin  Increased cardiac output  Increased Heart Rate due to direct stimulatory effect by catecholamines because of increased adrenergic receptors  Effects on Respiratory System  Increases rate of Oxygen consumption  Increases rate and depth of respiration  Effects on CNS  Increases synaptic activity  Hyperthyroidism causes anxiety and nervousness  Hypothyroidism causes mental retardation in children

Effects of Thyroid Hormone

 Effects on GIT  Increases appetite  Increases food intake  Increased rate of Absorption  Increases secretion digestive juices  Increases GIT motility  Hyperthyroidism causes diarrhea  Effects on Reproductive system  Essential for normal reproduction  Hypothyroidism leads to reduces fertility  Hypo  Decreased libido in both male and female  Impotence in men (hyperthoyroidism)

Hypothyroidism

 Hypothyroid disorders  Thyroid gland defect  Inadequate TSH or TRH release.  Thyroid gland removed surgically  Inadequate dietary iodine      In adults, the full-blown hypothyroid syndrome is called Myxedema (Mucous swelling)  Symptoms  Low metabolic rate;  Feeling chilled;  Constipation;  Thick, dry skin and puffy eyes;

Goiter

 If myxedema results from lack of iodine, the thyroid gland enlarges and protrudes, a condition called goiter.

 Depending on the cause, myxedema can be reversed by iodine supplements or

Cretinism

 Severe hypothyroidism in infants is called cretinism  Mental retardation  Short, disproportionately sized body  Thick tongue and neck.  Cretinism may reflect a genetic deficiency of the fetal thyroid gland or maternal factors, such as lack of dietary iodine.  It is preventable by thyroid hormone replacement therapy if diagnosed early enough, but once developmental abnormalities and mental retardation appear, they are not reversible.

Hyperthyroidism

 Graves’ disease:  An autoimmune disease  Serum IgG antibodies (TSI or TSAb) bind to TSH Receptors and stimulate thyroid hormone production  Symptoms include  Elevated metabolic rate;  sweating; rapid, irregular heartbeat;  nervousness; and weight loss despite adequate food intake.  Exophthalmos, protrusion of the eyeballs, may occur if the tissue behind the eyes becomes edematous and then fibrous

Thyroid Disorders

Exopht ha lmo s

Cretinism

Calcitonin

 A peptide hormone produced by the parafollicular, or C, cells  Lowers blood calcium levels in children  Antagonist to parathyroid hormone (PTH)  Functions  Calcitonin targets the skeleton, where it:  Inhibits osteoclast activity and release of calcium from the bone matrix  Stimulates calcium uptake and incorporation into the bone matrix  Regulated by a humoral (calcium ion concentration in the blood) negative feedback mechanism 2+

Pharmacy Application: Therapeutic effects of Calcitonin

 Paget’s disease  Characterized by a significant increase in osteoclast activity and, thus, a high rate of bone turnover and hypercalcemia  Treatment  Cibacalcin®, (synthetic human calcitonin)  Miacalcin, (Salmon calcitonin )  Postmenopausal osteoporosis  Salmon calcitonin, which is 20 times more potent than human calcitonin, has also been approved for therapeutic use in patients with postmenopausal

Parathyroid Glands

 Tiny glands embedded in the posterior aspect of the thyroid  Cells are arranged in cords containing oxyphil and chief cells  Chief (principal) cells secrete PTH  PTH (parathormone) regulates calcium balance in the blood  Normally four in number but up to 8 are reported

Parathyroid Glands

Calcium & Phosphate Metabolism

 Calcium accounts for 2% of body weight  Normal body calcium levels 9.4mg/dl or 2.4mmol/L  <0.1% in ECF, <1% in cells, remaining almost 99% in bones  Physiological Actions:  Transmission of nerve impulse  Muscle contraction  Blood clotting  Bone formation  Hypocalcemia Causes Nervous System excitement and Tetany  Hypercalcemia Depresses Nervous System and Muscle Activity

Calcium Metabolism

Calcium and Vitamin D:

Formation of Active Vitamin D:

25-Hydroxylase

PTH

1-α -Hydroxylase

()

(Active)

()

24-Hydroxylase

(Inactive)

Functions of Active Vitamin D:  Promote Intestinal Calcium Absorption  It binds with its nuclear receptor in the brush border of intestinal epithelial cells and induces the expression of  Calcium-binding protein (CaBP) (Rate of Ca2+ abs. α CaBP)

 Ca2+- ATPase  Decreases renal Calcium and Phosphate Excretion  Vitamin D in smaller quantities promotes bone calcification  The administration of extreme quantities of vitamin D causes absorption of bone  Osteomalacia (Adults) (Softening of

Parathyroid Hormone (Parathormone)  Preprohormone-110AA, Prohormone-90 AA, Hormone-84 AA  34-AA containing fragments have also been isolated adjacent to N-terminus  Secretion of PTH  PTH release is controlled serum Ca2+ through Negative feed back mechanism  Secretion is through 2nd Messenger cAMP by parathyroid gland  Actions of Parathyroid Hormone  It is the principal regulator of calcium metabolism. Its overall effects include:  Increase in blood levels of calcium  Decrease in blood levels of phosphate

Parathyroid Hormone  PTH increases Ca2+ levels in blood by stimulating three target organs:  The skeleton, (Calcium reserves)  The kidneys,  The intestine  PTH release increases Ca2+ in the blood as it:  Stimulates osteoclasts to digest bone matrix  Enhances the reabsorption of Ca2+ and the excretion of phosphate by the kidneys  Increases absorption of Ca2+ by intestinal mucosal cells with the help of vitamin D that is activated by PTH in kidneys  Rising Ca2+ in the blood inhibits PTH release

Effects of Parathyroid Hormone

Hypocalcaemia

Adrenal (Suprarenal) Glands

 Adrenal glands – paired, pyramid-shaped organs at top of the kidneys, weigh 4 g each.  Structurally and functionally, they are two glands in one  Adrenal medulla – nervous tissue that acts as part of the Sympathetic NS (20% of gland)  Adrenal cortex – bulk of glandular tissue derived from embryonic mesoderm encapsulating medulla

Adrenal Cortex  Synthesizes and releases steroid hormones called corticosteroids  More than 24 corticosteroids are synthesized  Different corticosteroids are produced in each of the three layers  Zona glomerulosa – mineralocorticoids (chiefly aldosterone)  Zona fasciculata – glucocorticoids (chiefly cortisol)  Zona reticularis – gonadocorticoids (chiefly androgens)

Bio-Synthesis of steroid Hormones

 Acetyl Co-A Liver Cholesterol (Precursor)  De Novo in Adrenal Cortex but not in placenta

Adrenal Cortex

Mineralocorticoids

 Regulation of the electrolyte concentrations of extracellular fluids particularly Na+ and K+  Aldosterone (95 %) – most important mineralocorticoid  Maintains Na+ balance by reducing excretion of sodium from the body  Stimulates reabsorption of Na+ by the kidneys  Promotes the synthesis of proteins needed for reabsorption of Na+ i.e Na+/K+ -ATPase  Its effects last for 20 minutes

Mineralocorticoids

The Four Mechanisms of Aldosterone Secretion

 Renin-angiotensin mechanism – kidneys release renin, which is converted into angiotensin II that in turn stimulates aldosterone release  Plasma concentration of sodium and potassium – directly influences the zona glomerulosa cells  ACTH – causes small increases of aldosterone during stress  Atrial natriuretic peptide (ANP) – inhibits activity of the zona glomerulosa

The Four Mechanisms of Aldosterone Secretion

Glucocorticoids  Glucocorticoid hormones include  cortisol (hydrocortisone)  cortisone, and  corticosterone,  Only cortisol is secreted in significant amounts in humans.  As for all steroid hormones, the basic mechanism of glucocorticoid activity on target cells is to modify gene activity  Cortisol  Help the body resist stress by:  Keeping blood sugar levels relatively constant  Maintaining blood volume and preventing water shift into tissue  Cortisol provokes:

Excessive Levels of Glucocorticoids

 Triggered in turn by the hypothalamic releasing hormone CRH.  Cortisol release is promoted by ACTH,  Rising cortisol levels feed back to act on both the hypothalamus and the anterior pituitary, preventing CRH release and shutting off ACTH and cortisol secretion.  Excessive levels of glucocorticoids:  Depress cartilage and bone formation  Inhibit inflammation  Depress the immune system  Promote changes in cardiovascular, neural, and gastrointestinal function

Cushing’s syndrome

 Glucocorticoid excess, Cushing’s syndrome,  ACTH-releasing pituitary tumor (in which case, it is called Cushing’s disease);  ACTH-releasing malignancy of the lungs, pancreas, or kidneys; or  A tumor of the adrenal cortex.  Most often results from the clinical administration of pharmacological doses (doses higher than those found in the body) of glucocorticoid drugs.  The syndrome is characterized by  persistent hyperglycemia (steroid diabetes),  dramatic losses in muscle and bone

Cushing’s syndrome

 The so-called cushingoid signs include  Swollen “moon” face,  Redistribution of fat to the abdomen and the posterior neck (causing a “buffalo hump”),  Tendency to bruise, and  Poor wound healing.  Because of enhanced anti-inflammatory effects,  infections may become overwhelmingly severe before producing recognizable symptoms.  The only treatment is removal of the cause—

Addison’s disease

 The major hyposecretory disorder of the adrenal cortex, usually involves  Deficits in both glucocorticoids and mineralocorticoids.  Its victims tend to  Lose weight;  Plasma glucose and sodium levels drop and potassium levels rise.  Severe dehydration and hypotension are common.  Treatment  Corticosteroid replacement therapy at physiological doses (doses typical of

Gonadocorticoids (Sex Hormones)

 Most gonadocorticoids secreted are androgens (male sex hormones), and the most important one is testosterone  Androgens contribute to:  The onset of puberty  The appearance of secondary sex characteristics  Sex drive in females  Androgens can be converted into estrogens after menopause

Adrenal Medulla

 Made up of chromaffin cells that secrete epinephrine and norepinephrine  Secretion of these hormones causes:  Blood glucose levels to rise  Blood vessels to constrict  The heart to beat faster  Blood to be diverted to the brain, heart, and skeletal muscle

PLAY

InterActive Physiology®: Endocrine System: Response to Stress

Adrenal Medulla

 Epinephrine is the more potent stimulator of the heart and metabolic activities  Norepinephrine is more influential on peripheral vasoconstriction and blood pressure

Stress and the Adrenal Gland

Pancreas

 A triangular gland, which has both exocrine and endocrine cells, located behind the stomach  Acinar cells produce an enzyme-rich juice used for digestion (exocrine product)  Pancreatic islets (islets of Langerhans) produce hormones (endocrine products)  The islets contain two major cell types:  Alpha (α) cells that produce glucagon  Beta (β) cells that produce insulin

Glucagon

 A 29-amino-acid polypeptide hormone that is a potent hyperglycemic agent  Its major target is the liver, where it promotes:  Glycogenolysis – the breakdown of glycogen to glucose  Gluconeogenesis – synthesis of glucose from lactic acid and noncarbohydrates  Release of glucose to the blood from liver cells

Insulin

 A 51-amino-acid protein consisting of two amino acid chains linked by disulfide bonds  Synthesized as part of proinsulin and then excised by enzymes, releasing functional insulin  Insulin:  Lowers blood glucose levels  Enhances transport of glucose into body cells  Counters metabolic activity that would enhance blood glucose levels

Effects of Insulin Binding

 The insulin receptor is a tyrosine kinase enzyme  After glucose enters a cell, insulin binding triggers enzymatic activity that:  Catalyzes the oxidation of glucose for ATP production  Polymerizes glucose to form glycogen  Converts glucose to fat (particularly in adipose tissue)

Regulation of Blood Glucose Levels

 The hyperglyce mic effects of glucagon and the hypoglyce mic effects of insulin

Diabetes Mellitus (DM)

 Results from hyposecretion or hypoactivity of insulin  The three cardinal signs of DM are:  Polyuria – huge urine output  Polydipsia – excessive thirst  Polyphagia – excessive hunger and food consumption  Hyperinsulinism – excessive insulin secretion, resulting in hypoglycemia

Diabetes Mellitus (DM)

Gonads: Female

 Paired ovaries in the abdominopelvic cavity produce estrogens and progesterone  They are responsible for:  Maturation of the reproductive organs  Appearance of secondary sexual characteristics  Breast development and cyclic changes in the uterine mucosa

Gonads: Male

 Testes located in an extra-abdominal sac (scrotum) produce testosterone  Testosterone:  Initiates maturation of male reproductive organs  Causes appearance of secondary sexual characteristics and sex drive  Is necessary for sperm production  Maintains sex organs in their functional state

Pineal Gland

 Small gland hanging from the roof of the third ventricle of the brain  Secretory product is melatonin  Melatonin is involved with:  Day/night cycles  Physiological processes that show rhythmic variations (body temperature, sleep, appetite)

Thymus

 Lobulated gland located deep to the sternum in the thorax  Major hormonal products are thymopoietins and thymosins  These hormones are essential for the development of the T lymphocytes (T cells) of the immune system

Other Hormone-Producing Structures

 Heart – produces atrial natriuretic peptide (ANP), which reduces blood pressure, blood volume, and blood sodium concentration  Gastrointestinal tract – enteroendocrine cells release local-acting digestive hormones  Placenta – releases hormones that influence the course of pregnancy

Other Hormone-Producing Structures

 Kidneys – secrete erythropoietin, which signals the production of red blood cells  Skin – produces cholecalciferol, the precursor of vitamin D  Adipose tissue – releases leptin, which is involved in the sensation of satiety, and stimulates increased energy expenditure

Developmental Aspects

 Hormone-producing glands arise from all three germ layers  Endocrine glands derived from mesoderm produce steroid hormones  Endocrine organs operate smoothly throughout life  Most endocrine glands show structural changes with age, but hormone production may or may not be affected

Developmental Aspects

 Exposure to pesticides, industrial chemicals, arsenic, dioxin, and soil and water pollutants disrupts hormone function  Sex hormones, thyroid hormone, and glucocorticoids are vulnerable to the effects of pollutants  Interference with glucocorticoids may help explain high cancer rates in certain areas

Developmental Aspects

 Ovaries undergo significant changes with age and become unresponsive to gonadotropins  Female hormone production declines, the ability to bear children ends, and problems associated with estrogen deficiency (e.g., osteoporosis) begin to occur  Testosterone also diminishes with age, but effect is not usually seen until very old age

Developmental Aspects

 GH levels decline with age and this accounts for muscle atrophy with age  Supplemental GH may spur muscle growth, reduce body fat, and help physique  TH declines with age, causing lower basal metabolic rates  PTH levels remain fairly constant with age, and lack of estrogen in women makes them more vulnerable to bonedemineralizing effects of PTH