Gore-1. General Endocrinology.pdf

General Endocrinology Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives By the end of this lecture you will: Learn about fundamental principles of endocrinology. Understand general properties of hormones. Describe the principle...

General Endocrinology Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives By the end of this lecture you will: Learn about fundamental principles of endocrinology. Understand general properties of hormones. Describe the principles that regulate hormone secretion and hormone actions. Gain an introductory understanding of the concept of endocrine dysfunctions. 2 Which are endocrine glands? 3 Pineal Hypothalamus Pituitary The Endocrine System Thyroid Parathyroid Posterior view Thymus Heart Liver Stomach Adrenal gland KEY Pancreas Duodenum Kidney Adipose tissue Skin Ovaries in female Placenta in pregnant female KEY Solely endocrine function 12 Mixed function 12 Testes in male 4 Endocrine systems enable the organisms to adapt to the environment Nervous Immune Endocrine Homeostasis: the maintenance of a steady state within an organism by means of physiological or behavioral feedback control mechanisms (Claude Bernard and William Cannon). 5 Principles of Endocrinology Endocrinology: the study of hormones in the body that are responsible for the maintenance of homeostasis and reproduction. Endocrine glands: Ductless glands scattered throughout body. Secrete hormones. Release of hormones occurs directly into bloodstream. Hormones travel through blood to target cells. Most (but not all) hormones are transported through the general circulatory system. Target cells have receptors for binding of the specific hormone. Hormones regulate or direct a particular function in the target cells. The target may be very close or a long distance from the endocrine gland. 6 Categorization, Properties, and Synthesis of Hormones Characterized based on solubility (lipophilic, hydrophilic) Solubility is important to pharmacists because it: Determines how the hormone is synthesized and processed in the endocrine gland Determines transport through blood Determines actions on the target cell 7 Hydrophilic (”water-loving”) hormones Catecholamine: Dopamine Peptide, protein, and amine (e.g. catecholamine) hormones Receptors are on cell membranes HO CH2-CH2-NH2 HO Peptides derive from precursors called preprohormones. They are pruned to active form during processing in ER and Golgi complex, then packaged and stored in secretory vesicles. On stimulation, secretory vesicles fuse with plasma membrane to release their contents outside by exocytosis. 8 Hydrophilic (”water-loving”) hormones ACG: I want you to know that these hormones bind to membrane receptors and undergo signal transduction through intracellular pathways. Receptors are in the GPCR, receptor tyrosine kinase, ionotropic receptor, etc., families 9 Lipophilic (“lipid-loving”) Hormones Include: Steroid hormones – cholesterol is the precursor; cleaved by a series of enzymatic reactions into product à steroidogenesis. Thyroid hormones – iodinated tyrosine derivative. Steroids are generally not stored and can be converted in blood or other organs. Associated with binding globulins in circulation (e.g. albumins, or hormone-specific binding globulins) Steroids pass through plasma membrane and exert intracellular actions 10 Lipophilic (“lipid-loving”) Hormones ACG: I want you to know that these hormones pass through membranes - passively (steroids) or actively with help of a transporter (thyroid hormones) - to bind to their receptors localized intracellularly, in the cytosol and/or nucleus. From there, receptors bind to DNA and act as transcription factors. 11 Tropic hormones A hormone whose primary function is to regulate the production and secretion of another hormone. They stimulate and maintain their target tissues. Sometimes tropic is in the hormone name and sometimes it is not. Adrenocorticotropic hormone (ACTH) stimulates the adrenal gland Gonadotropins (LH and FSH) stimulate the gonads Thyroid stimulating hormone (TSH) stimulates the thyroid gland (this used to be called thyrotropic hormone) 12 Complexity of Endocrine Function One endocrine gland may produce >1 hormone Anterior pituitary à 6+ hormones. One hormone may be secreted by >1 gland Somatostatin à hypothalamus and pancreas. One hormone may have multiple target cell types Insulin --> muscle, liver, fat. One target cell may be influenced by >1 hormone Cells can contain an array of receptors 13 Complexity of Endocrine Function (cont) Hormone secretion has many rhythms Hourly, daily, yearly. Some hormones are neurotransmitters in other systems Dopamine - classical neurotransmitter; also a hormone in the neuroendocrine regulation of lactation. In both instances requires dopamine receptors. Some organs have both endocrine and nonendocrine functions Pancreas, brain, many others. 14 Regulation of hormone concentrations The effective plasma concentration of a free, biologically active from of a hormone – and its receptor availability – depends on: The rate of hormone secretion into the blood The rate of metabolic activation or conversion by enzymes Steroid hormones - steroidogenesis Thyroid hormone conversion from T4 to T3 Plasma protein binding Rate of removal from blood by metabolic inactivation and excretion 15 Regulation of hormone secretion Several factors affect the rate of a hormone’s secretion including: Negative-feedback control Neuroendocrine reflexes Diurnal Rhythms 16 Negative feedback control Negative feedback occurs when the output of a system counteracts a change in input. This is a fundamental property of almost all endocrine systems and is a principle of diagnostic testing and therapeutics. Hormone 1 (-) (-) (+) Hormone 2 (-) (+) Hormone 3 17 Neuroendocrine reflexes Neuroendocrine reflexes can produce sudden increases in hormone secretion in response to specific stimuli. Involve a neural and endocrine component. Example: Suckling of an infant triggers almost instantaneous milk letdown through a neuroendocrine reflex that causes release of oxytocin. 18 Diurnal (circadian) rhythms The most common endocrine rhythms are diurnal (“daynight”) or circadian (“about a day”). Hormone secretion occur at regular intervals over the 24 h cycle. This activity is regulated by an endogenous oscillator. Courtesy of Dr. Laura Fonken More details next unit… stay tuned! 19 Factors influencing target cell responses Receptor down-regulation: a reduction in the number of receptors for (and sensitivity to) a given hormone as a result of elevated levels of that hormone. One hormone can influence activity of another hormone at a given target cell: Permissiveness One hormone must be present in adequate amount to “permit” effects of another hormone. Synergism Occurs when actions of several hormones are complementary Combined effect is greater than the sum of their separate effects Antagonism One hormone causes the loss of another hormone’s receptors. 20 Endocrine Dysfunction Typically arise from: Hyposecretion: too little hormone secreted Hypersecretion: too much hormone secreted Target cell responsiveness to the hormone is low. 21 Hyposecretion Primary hyposecretion Too little hormone is secreted due to abnormality within the gland itself Secondary hyposecretion The gland is normal but too little hormone is secreted due to deficiency of its tropic hormonal input Causes: genetic, dietary, chemical or toxic, immunologic, other disease processes such as cancer, iatrogenic (healthcareinduced, e.g., removal of gland), idiopathic These distinctions are important to therapeutic treatment of disease. 22 Hypersecretion Primary hypersecretion Too much hormone is secreted due to abnormality within the gland itself Secondary hypersecretion Too much hormone is secreted due to excess external stimulation Causes: tumors, immunologic factors. 23 Learning Objectives By the end of this lecture you will: Learn about fundamental principles of endocrinology. Understand general properties of hormones. Describe the principles that regulate hormone secretion and hormone actions. Gain an introductory understanding of the concept of endocrine dysfunctions. 24