Endocrine Secretion and Action-Comprehensive

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Endocrine Glands: Secretion and Action of Hormones Marc Imhotep Cray, M.D.:

Endocrine Glands: Secretion and Action of Hormones Marc Imhotep Cray, M.D. Also see: Histology Endocrine Glands This Presentation is part of IVMS ENDOCRINE BASIC MEDICAL SCIENCE Collection

Endocrine Glands and Hormones:

Endocrine Glands and Hormones Secrete biologically active molecules into the blood. Lack ducts. Carry hormones to target cells that contain specific receptor proteins for that hormone. Target cells can respond in a specific fashion. 2

Endocrine Glands and Hormones (continued):

Endocrine Glands and Hormones (continued) Neurohormone: Specialized neurons that secrete chemicals into the blood rather than synaptic cleft. Chemical secreted is called neurohormone. Hormones: Affect metabolism of target organs. Help regulate total body metabolism, growth, and reproduction. 3

Chemical Classification of Hormones:

Chemical Classification of Hormones Amines: Hormones derived from tyrosine and tryptophan. NE, Epi, T 4 . Polypeptides and proteins: Polypeptides: Chains of < 100 amino acids in length. ADH. Protein hormones: Polypeptide chains with > 100 amino acids. Growth hormone. 4

Chemical Classification of Hormones (continued):

Chemical Classification of Hormones (continued) Lipids derived from cholesterol. Are lipophilic hormones. Testosterone. Estradiol. Cortisol. Progesterone. 5

Chemical Classification of Hormones (continued):

Chemical Classification of Hormones (continued) 6

Chemical Classification of Hormones (continued):

Chemical Classification of Hormones (continued) Glycoproteins: Long polypeptides (>100) bound to 1 or more carbohydrate (CHO) groups. FSH and LH. Hormones can also be divided into: Polar: H 2 0 soluble. Nonpolar (lipophilic): H 2 0 insoluble. Can gain entry into target cells. Steroid hormones and T 4 . Pineal gland secretes melatonin: Has properties of both H 2 0 soluble and lipophilic hormones. 7

Prohormones and Prehormones:

Prohormones and Prehormones Prohormone: Precursor is a longer chained polypeptide that is cut and spliced together to make the hormone. Proinsulin. Preprohormone: Prohormone derived from larger precursor molecule. Preproinsulin. Prehormone: Molecules secreted by endocrine glands that are inactive until changed into hormones by target cells. T 4 converted to T 3 . 8

Common Aspects of Neural and Endocrine Regulation:

Common Aspects of Neural and Endocrine Regulation APs are chemical events produced by diffusion of ions through neuron plasma membrane. Action of some hormones are accompanied by ion diffusion and electrical changes in the target cell. Nerve axon boutons release NTs. Some chemicals are secreted as hormones, and also are NTs. In order for either a NT or hormone to function in physiological regulation: Target cell must have specific receptor proteins. Combination of the regulatory molecule with its receptor proteins must cause a specific sequence of changes. There must be a mechanism to quickly turn off the action of a regulator. 9

PowerPoint Presentation:

Synergistic: Two hormones work together to produce a result. Additive: Each hormone separately produces response, together at same concentrations stimulate even greater effect. NE and Epi . Complementary: Each hormone stimulates different step in the process. FSH and testosterone. 10

Hormonal Interactions (continued):

Hormonal Interactions (continued) Permissive effects: Hormone enhances the responsiveness of a target organ to second hormone. Increases the activity of a second hormone. Prior exposure of uterus to estrogen induces formation of receptors for progesterone. Antagonistic effects: Action of one hormone antagonizes the effects of another. Insulin and glucagon. 11

Effects of [Hormone] on Tissue Response:

Effects of [Hormone] on Tissue Response [Hormone] in blood reflects the rate of secretion. Half-life: Time required for the blood [hormone] to be reduced to ½ reference level. Minutes to days. Normal tissue responses are produced only when [hormone] are present within physiological range. Varying [hormone] within normal, physiological range can affect the responsiveness of target cells. 12

Effects of [Hormone] on Tissue Response (continued):

Effects of [Hormone] on Tissue Response (continued) Priming effect (upregulation): Increase number of receptors formed on target cells in response to particular hormone. Greater response by the target cell. Desensitization (downregulation): Prolonged exposure to high [polypeptide hormone]. Subsequent exposure to the same [hormone] produces less response. Decrease in number of receptors on target cells. Insulin in adipose cells. Pulsatile secretion may prevent downregulation. 13

Mechanisms of Hormone Action:

Mechanisms of Hormone Action Hormones of same chemical class have similar mechanisms of action. Similarities include: Location of cellular receptor proteins depends on the chemical nature of the hormone. Events that occur in the target cells. To respond to a hormone: Target cell must have specific receptors for that hormone (specificity). Hormones exhibit: Affinity (bind to receptors with high bond strength). Saturation (low capacity of receptors). 14

Hormones That Bind to Nuclear Receptor Proteins:

Hormones That Bind to Nuclear Receptor Proteins Lipophilic steroid and thyroid hormones are attached to plasma carrier proteins. Hormones dissociate from carrier proteins to pass through lipid component of the target plasma membrane. Receptors for the lipophilic hormones are known as nuclear hormone receptors. 15

Nuclear Hormone Receptors:

Nuclear Hormone Receptors Steroid receptors are located in cytoplasm and in the nucleus. Function within cell to activate genetic transcription. Messenger RNA directs synthesis of specific enzyme proteins that change metabolism. Each nuclear hormone receptor has 2 regions: A ligand (hormone)-binding domain. DNA-binding domain. Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element). Located adjacent to gene that will be transcribed. 16

Mechanisms of Steroid Hormone Action:

Mechanisms of Steroid Hormone Action Cytoplasmic receptor binds to steroid hormone. Translocates to nucleus. DNA-binding domain binds to specific HRE of the DNA. Dimerization occurs. Process of 2 receptor units coming together at the 2 half-sites. Stimulates transcription of particular genes. 17

Mechanism of Thyroid Hormone Action:

Mechanism of Thyroid Hormone Action T 4 passes into cytoplasm and is converted to T 3 . Receptor proteins located in nucleus. T 3 binds to ligand-binding domain. Other half-site is vitamin A derivative (9-cis-retinoic) acid. DNA-binding domain can then bind to the half-site of the HRE. Two partners can bind to the DNA to activate HRE. Stimulate transcription of genes. 18

Hormones That Use 2nd Messengers:

Hormones That Use 2 nd Messengers Hormones cannot pass through plasma membrane use 2 nd messengers. Catecholamine, polypeptide, and glycoprotein hormones bind to receptor proteins on the target plasma membrane. Actions are mediated by 2 nd messengers (signal-transduction mechanisms). Extracellular hormones are transduced into intracellular 2 nd messengers. 19

Adenylate Cyclase-cAMP:

Polypeptide or glycoprotein hormone binds to receptor protein causing dissociation of a subunit of G-protein. G-protein subunit binds to and activates adenylate cyclase. ATP cAMP + PP i cAMP attaches to inhibitory subunit of protein kinase. Inhibitory subunit dissociates and activates protein kinase. Adenylate Cyclase-cAMP 20

Adenylate Cyclase-cAMP (continued):

Adenylate Cyclase-cAMP (continued) Phosphorylates enzymes within the cell to produce hormone’s effects. Modulates activity of enzymes present in the cell. Alters metabolism of the cell. cAMP inactivated by phosphodiesterase. Hydrolyzes cAMP to inactive fragments. 21


Binding of Epi to a -adrenergic receptor in plasma membrane activates a G-protein intermediate, phospholipase C. Phospholipase C splits phospholipid into IP 3 and DAG. Both derivatives serve as 2 nd messengers. IP 3 diffuses through cytoplasm to ER. Binding of IP 3 to receptor protein in ER causes Ca 2+ channels to open. Phospholipase-C-Ca 2+ 22

Phospholipase-C-Ca2+ (continued):

Phospholipase-C-Ca 2+ (continued) Ca 2+ diffuses into the cytoplasm. Ca 2+ binds to calmodulin. Calmodulin activates specific protein kinase enzymes. Alters the metabolism of the cell, producing the hormone’s effects. 23

Epi Can Act Through Two 2nd Messenger Systems:

Epi Can Act Through Two 2 nd Messenger Systems 24

Tyrosine Kinase:

Tyrosine Kinase Insulin receptor consists of 2 units that dimerize when they bind with insulin. Insulin binds to ligand–binding site on plasma membrane, activating enzymatic site in the cytoplasm. Autophosphorylation occurs, increasing tyrosine kinase activity. Activates signaling molecules. Stimulate glycogen, fat and protein synthesis. Stimulate insertion of GLUT-4 carrier proteins. 25

Tyrosine Kinase (continued):

Tyrosine Kinase (continued) 26

Pituitary Gland:

Pituitary Gland Pituitary gland is located in the diencephalon. Structurally and functionally divided into: Anterior lobe. Posterior lobe. 27

Pituitary Gland (continued):

Anterior pituitary: Master gland (adenohypophysis). Derived from a pouch of epithelial tissue that migrates upward from the mouth. Consists of 2 parts: Pars distalis: anterior pituitary. Pars tuberalis: thin extension in contact with the infundibulum . Posterior pituitary(neurohypophysis): Formed by downgrowth of the brain during fetal development. Is in contact with the infundibulum. Nerve fibers extend through the infundibulum. Pituitary Gland (continued) 28

Pituitary Hormones:

Pituitary Hormones Anterior Pituitary: Trophic effects: High blood [hormone] causes target organ to hypertrophy. Low blood [hormone] causes target organ to atrophy. 29

Pituitary Hormones (continued):

Pituitary Hormones (continued) Posterior pituitary: Stores and releases 2 hormones that are produced in the hypothalamus: Antidiuretic hormone (ADH/vasopressin): Promotes the retention of H 2 0 by the kidneys. Less H 2 0 is excreted in the urine. Oxytocin: Stimulates contractions of the uterus during parturition. Stimulates contractions of the mammary gland alveoli. Milk-ejection reflex. 30

Hypothalamic Control of Posterior Pituitary:

Hypothalamic Control of Posterior Pituitary Hypothalamus neuron cell bodies produce: ADH: supraoptic nuclei. Oxytocin: paraventricular nuclei. Transported along the hypothalamo-hypophyseal tract. Stored in posterior pituitary. Release controlled by neuroendocrine reflexes. 31

Hypothalamic Control of the Anterior Pituitary:

Hypothalamic Control of the Anterior Pituitary Hormonal control rather than neural. Hypothalamus neurons synthesize releasing and inhibiting hormones. Hormones are transported to axon endings of median eminence. Hormones secreted into the hypothalamo-hypophyseal portal system regulate the secretions of the anterior pituitary 32

Feedback Control of the Anterior Pituitary:

Anterior pituitary and hypothalamic secretions are controlled by the target organs they regulate. Secretions are controlled by negative feedback inhibition by target gland hormones. Negative feedback at 2 levels: The target gland hormone can act on the hypothalamus and inhibit secretion of releasing hormones. The target gland hormone can act on the anterior pituitary and inhibit response to the releasing hormone. Feedback Control of the Anterior Pituitary 33

Feedback Control of the Anterior Pituitary (continued):

Feedback Control of the Anterior Pituitary (continued) Short feedback loop: Retrograde transport of blood from anterior pituitary to the hypothalamus. Hormone released by anterior pituitary inhibits secretion of releasing hormone. Positive feedback effect: During the menstrual cycle, estrogen stimulates “LH surge.” 34

Higher Brain Function and Pituitary Secretion:

Higher Brain Function and Pituitary Secretion Axis: Relationship between anterior pituitary and a particular target gland. Pituitary-gonad axis. Hypothalamus receives input from higher brain centers. Psychological stress affects: Circadian rhythms. Menstrual cycle. 35

Adrenal Glands:

Adrenal Glands Paired organs that cap the kidneys. Each gland consists of an outer cortex and inner medulla. Adrenal medulla: Derived from embryonic neural crest ectoderm (same tissue that produces the sympathetic ganglia). Synthesizes and secretes: Catecholamines (mainly Epi but some NE). 36

Adrenal Glands (continued):

Adrenal Glands (continued) Adrenal cortex: Does not receive neural innervation. Must be stimulated hormonally (ACTH). Consists of 3 zones: Zona glomerulosa. Zona fasciculata. Zona reticularis. Secretes corticosteroids. 37

Functions of the Adrenal Cortex:

Functions of the Adrenal Cortex Zona glomerulosa: Mineralcorticoids (aldosterone): Stimulate kidneys to reabsorb Na + and secrete K + . Zona fasciculata: Glucocorticoids (cortisol): Inhibit glucose utilization and stimulate gluconeogenesis. Zona reticularis (DHEA): Sex steroids: Supplement sex steroids. 38

Functions of the Adrenal Cortex (continued):

Functions of the Adrenal Cortex (continued) 39

Functions of the Adrenal Medulla:

Functions of the Adrenal Medulla Innervated by preganglionic sympathetic axons. Increase respiratory rate. Increase HR and cardiac output. Vasoconstrict blood vessels, thus increasing venous return. Stimulate glycogenolysis. Stimulate lipolysis. 40

Stress and the Adrenal Gland:

Stress and the Adrenal Gland Non-specific response to stress produces the general adaptation syndrome (GAS). Alarm phase: Adrenal glands activated. Stage of resistance: Stage of readjustment. Stage of exhaustion: Sickness and/or death if readjustment is not complete. 41

Thyroid Hormones:

Thyroid Hormones Thyroid gland is located just below the larynx. Thyroid is the largest of the pure endocrine glands. Follicular cells secrete thyroxine. Parafollicular cells secrete calcitonin. 42

Production of Thyroid Hormones:

Production of Thyroid Hormones Iodide (I - ) actively transported into the follicle and secreted into the colloid. Oxidized to iodine (I o ). Iodine attached to tyrosine within thyroglobulin chain. Attachment of 1 iodine produces monoiodotyrosine (MIT). Attachment of 2 iodines produces diiodotyrosine (DIT). MIT and DIT or 2 DIT molecules coupled together. 43

Production of Thyroid Hormones (continued):

Production of Thyroid Hormones (continued) T 3 and T 4 produced. TSH stimulates pinocytosis into the follicular cell. Enzymes hydrolyze T 3 and T 4 from thyroglobulin. Attached to TBG and released into blood. 44

Production of Thyroid Hormones (continued):

Production of Thyroid Hormones (continued) 45

Actions of T3:

Actions of T 3 Stimulates protein synthesis. Promotes maturation of nervous system. Stimulates rate of cellular respiration by: Production of uncoupling proteins. Increase active transport by Na + /K + pumps. Lower cellular [ATP]. Increases metabolic heat. Increases metabolic rate. Stimulates increased consumption of glucose, fatty acids and other molecules. 46

Diseases of the Thyroid :

Diseases of the Thyroid Iodine-deficiency (endemic) goiter: Abnormal growth of the thyroid gland. In the absence of sufficient iodine, cannot produce adequate amounts of T 4 and T 3 . Lack of negative feedback inhibition. Stimulates TSH, which causes abnormal growth. 47

Diseases of the Thyroid (continued):

Diseases of the Thyroid (continued) [Iodine-deficiency (endemic) goiter—continued] Adult myxedema: Accumulation of mucoproteins and fluid in subcutaneous tissue. Symptoms: Decreased metabolic rate. Weight gain. Decreased ability to adapt to cold. Lethargy. Grave’s disease: Autoimmune disorder: Exerts TSH-like effects on thyroid. Not affected by negative feedback. Cretinism: Hypothyroid from end of 1 st trimester to 6 months postnatally. Severe mental retardation. 48

Parathyroid Glands:

Parathyroid Glands Embedded in the lateral lobes of the thyroid gland. Parathyroid hormone (PTH): Only hormone secreted by the parathyroid glands. Single most important hormone in the control of blood [Ca 2+ ]. Stimulated by decreased blood [Ca 2+ ]. Promotes rise in blood [Ca 2+ ] by acting on bones, kidney and intestines. 49

Pancreatic Islets (Islets of Langerhans):

Pancreatic Islets (Islets of Langerhans) Alpha cells secrete glucagon. Stimulus is decrease in blood [glucose]. Stimulates glycogenolysis and lipolysis. Stimulates conversion of fatty acids to ketones . Beta cells secrete insulin. Stimulus is increase in blood [glucose]. Promotes entry of glucose into cells. Converts glucose to glycogen and fat. Aids entry of amino acids into cells. 50

Pineal Gland:

Pineal Gland Secretes melatonin: Production stimulated by the suprachiasmatic nucleus (SCN) in hypothalamus. SCN is primary center for circadian rhythms. Light/dark changes required to synchronize. Melatonin secretion increases with darkness and peaks in middle of night. May inhibit GnRH. May function in the onset of puberty (controversial). 51

Pineal Gland (continued):

Pineal Gland (continued) 52


Thymus Site of production of T cells (thymus-dependent cells), which are lymphocytes. Lymphocytes are involved in cell-mediated immunity. Secretes hormones that are believed to stimulate T cells after leave thymus. Thymus gland size is large in newborns and children. Regresses after puberty and becomes infiltrated with strands of fibrous tissue. 53

Gonads and Placenta:

Gonads and Placenta Gonads (testes and ovaries): Secrete sex hormones. Testosterone. Estradiol 17- b . After menopause, produces estrone. Progesterone. Placenta: Secretes large amounts of estriol, progesterone, hCG, hCS. 54

Autocrine and Paracrine Regulation:

Autocrine and Paracrine Regulation Autocrine: Produced and act within the same tissue of an organ. All autocrine regulators control gene expression in target cells. Paracrine: Produced within one tissue and regulate a different tissue of the same organ. Cytokines (lymphokines): Regulate different cells (interleukins) . Growth factors: Promote growth and cell division in any organ. Neutrophins: Guide regenerating peripheral neurons. 55


Prostaglandins Most diverse group of autocrine regulators. Produced in almost every organ. Wide variety of functions. Different prostaglandins may exert antagonistic effects in some tissues. Immune system: Promote inflammatory process. Reproductive system: Play role in ovulation. Digestive system: Inhibit gastric secretion. 56

Prostaglandins (continued):

Prostaglandins (continued) 57

Prostaglandins (continued):

Prostaglandins (continued) Respiratory system: May bronchoconstrict or bronchodilate. Circulatory system: Vasoconstrictors or vasodilators. Urinary system: Vasodilation. Inhibitors of prostaglandin synthesis: Non-steroidal anti-inflammatory drugs (NSAIDS). Aspirin, indomethacin, ibuprofen: inhibit COX1. Celecoxib and rofecoxib: inhibit COX2. 58

ENDOCRINOLOGY HYPERLINK Photos, Images and Pictures:

ENDOCRINOLOGY HYPERLINK Photos, Images and Pictures Atlas of the Endocrine System [Peyrin et Vandroux] - Univ de St.Etienne (FR) Endocrine Pathol. images - U of Pittsburg Endocrine Pathol. index [EC Klatt] Some Pictures and illustrations in Endocrinology - Univ of Houston (US) Some Images in Endocrinology - MedStudents (BR) Advanced Imaging of the Diabetic Foot and Its Complications [A Gentili] - UCSD Images related to the Endocrine System - Cushings-Help.com A collection of Thyroid surgery images from the American Thyroid Clinic Some Images of Thyroid Disorders [DW Gardner] Thyroid Imaging .com [G Perrella] 59

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