Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones. From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.
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Endocrine Pharmacology Basic Concepts Endocrine system’s target organ are usually located relatively far from site of release of chemical mediator (hormone) of the signal A hormone is a substance secreted by one tissue or gland that is transported via circulation to a site where it exerts its effects on different tissues Signaling mechanisms which use enzymes, neurotransmitters, hormones, and receptors are similar (aside from distance) Hence, basic pharmacologic principles of therapy are same Keys to understanding endocrine pharmacology are feed-forward and feed-back mechanisms that govern how “releasing” factors in hypothalamus control release of hormones in pituitary that in turn cause release of second-tier hormones that target multiple organs within body Hypothalamic Releasing Hormone Pituitary Trophic (Signal) Hormone Target Hormone(s) Marc Imhotep Cray, MD
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Routes by which chemical signals are delivered to cells 1. Autocrine chemical messengers stimulates the cell that originally secreted it 2. Paracrine chemical messengers act locally on nearby cells 3. Neurotransmitters secreted by neurons that activate an adjacent cellďƒ another neuron, a muscle cell, or a glandular cell 4. Endocrine chemical messengers are hormones secreted into bloodstream by certain glands and cells– and act at a distant site Marc Imhotep Cray, MD
Modified from: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
Overall Function of Hormones A hormone is a substance secreted by one tissue but has actions at remote tissues Hormones maintain homeostasis by regulating processes such as development, metabolism, and reproduction Hormones: maintain homeostasis through feedback loops Hormones: act slowly relative to nervous system
Marc Imhotep Cray, MD
Remember: Nervous System chemical mediator (neurotransmitter) Endocrine system chemical mediator (hormone) Basic physiologic, biochemical and pharmacologic principles are same.
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Endocrine Pharmacology Basic Concepts (2) Hormone Receptors
There are two major classes of hormones: 1. proteins, peptides, and modified amino acids 2. steroids
All known hormones, and drugs that mimic hormones, act via one of two basic receptor systems:
membrane-associated receptors and intracellular receptors
1. Membrane-associated receptors Membrane-associated receptors bind hydrophilic hormones (which penetrate plasma membrane poorly), such as Marc Imhotep Cray, MD
Insulin Adrenocorticotropic hormone (ACTH), and Epinephrine, outside the cell 5
Basic Concepts (3) Hormone Receptors cont. 1. Membrane-associated receptors transmit signals into cell by a variety of “second messenger” mechanisms, including: Changes in cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) caused by changes in activity of cyclases Increased phosphoinositide turnover via increased phospholipase activity Increased intracellular Ca2+ by action on Ca2+ channels Increased tyrosine phosphorylation on specific proteins by action of tyrosine kinases (TKR) Marc Imhotep Cray, MD
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The four major classes of membrane receptors for hormones and neurotransmitters
Marc Imhotep Cray, MD
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
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Basic Concepts (4) Hormone Receptors cont. 2. Intracellular receptors: Intracellular receptors bind hydrophobic (lipophilic) hormones (which penetrate plasma membrane easily) such as Cortisol Retinol, and Estrogen inside cell—either in cytoplasm or nucleus Intracellular receptors modulate transcription rate of specific target genes to change levels of cellular proteins N.B. Hormones (and Vitamins) that work via steroid receptor: estrogen, testosterone, glucocorticoids, vitamin D, aldosterone, progesterone, T3/T4 Marc Imhotep Cray, MD
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*Mechanism using a G protein, as shown in D (Next slide)
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McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
Hormone second-messenger systems
Hormone 2nd messenger systems-Mechanism using a G protein G-protein mechanism. 1. Messenger system before hormone binding 2. After hormone binding, GTP replaces GDP on G protein. 3. GTP, attached to α subunit, dissociates from the β−γ complex and converts ATP to cAMP. 4. Hormone is released from binding site and complex returns to inactive state when GTPase cleaves GTP to GDP. Marc Imhotep Cray, MD
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
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Hormone 2nd messenger systems: G-Protein Class, Action and Examples G Protein Subtype
Action
Examples
Modified from: McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
Marc Imhotep Cray, MD
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Class of Receptors Used by Various Hormones Receptor Class
Hormones and Related Substances
cAMP
LH, FSH, ACTH, TSH, PTH, hCG, CRH, glucagon
cGMP
NO, ANP
IP3
GnRH, GHRH, oxytocin, TRH
Steroid receptor
Estrogen, testosterone, glucocorticoids, vitamin D, aldosterone, progesterone, T3/T4
Tyrosine kinase
Insulin, growth factors (e.g., IGF, PDGF), GH, prolactin
Redrawn after: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
Ledger: ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor; IP3, inositol triphosphate; NO, nitric oxide; PDGF, platelet-derived growth factor; PTH, parathyroid hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone. Marc Imhotep Cray, MD
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Cellular MOA of steroid hormones Steroid hormones are lipophilic therefore, they diffuse across plasma membrane and form complexes with cytosolic or nuclear receptors bound complexes then activate transcription of various genes Because steroid hormones rely on the intermediary process of gene expression and protein translation it can take hours to days for their effects to manifest Examples of steroid hormones are testosterone, estrogen, progesterone, cortisol, and aldosterone Cholesterol is precursor to all steroid hormones Although thyroid hormone is not a steroid hormone TH uses same cellular mechanism as steroids Marc Imhotep Cray, MD
Remember: There are two major classes of hormones: 1. proteins, peptides, and modified amino acids 2. steroids
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MOA of peptide hormones and catecholamines Peptide hormones and catecholamines are not highly lipid-diffusible and thus cannot cross plasma membrane They bind to cell surface receptors (next slide), which initiate a variety of biochemical events, including o activation or inhibition of enzymes o alteration of membrane proteins, and o mediation of cellular trafficking These processes can occur within seconds to minutes o Nevertheless, peptide hormones can stimulate gene expression as well, and this effect is delayed as it is with steroid hormones Examples of peptide hormones are insulin, parathyroid hormone (PTH), vasopressin (antidiuretic hormone), and oxytocin Marc Imhotep Cray, MD
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Mechanisms by which peptide and steroid hormones signal
Marc Imhotep Cray, MD
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
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Basic Concepts (5) Hypopituitarism may be partial or complete and may result from hypothalamic disease (leading to deficiency of hypothalamic-releasing hormones) or intrinsic pituitary disease(causing pituitary hormone deficiency) Hypopituitarism may affect any of these pituitary hormones: thyrotropin (TSH) growth hormone(GH) luteinizing hormone (LH) follicle stimulating hormone (FSH) and corticotropin (ACTH) Marc Imhotep Cray, MD
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Basic Concepts (6) In targeting one of these hormones of hypopituitarism therapy for GH deficiency aims to restore normal body composition, as well as, in children, to promote linear growth Therapy for acromegaly, caused by excessive GH secretion, includes surgery and (or) radiation, or use of a GH inhibitor
Marc Imhotep Cray, MD
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Basic Concepts (7) Hypothyroidism can result from either thyroid (high TSH, low T3 &T4) or hypothalamic (or) dysfunction (low T3, T4, TSH)
Treatment of choice is hormone substitution by using a synthetic hormone Hyperthyroidism (thyrotoxicosis) is characterized by increased metabolism, and primary treatment options include surgery radioactive iodine or drugs that inhibit formation of T3 &T4 by blocking utilization of iodine Marc Imhotep Cray, MD
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Basic Concepts (8) Principal functions of glucocorticoids involve regulation of carbohydrate metabolism and a variety of other physiologic actions Synthetic corticosteroids (eg, hydrocortisone, prednisone, and dexamethasone) are widely used as therapeutic agents in Tx of cancer and autoimmune or inflammatory-type disorders Pharmacologic treatment is also available for insufficient adrenal function manifested as Addison disease excess glucocorticoid exposure results in Cushing syndrome Marc Imhotep Cray, MD
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Basic Concepts (9) Diabetes mellitus (DM) is a syndrome caused by a relative or absolute deficiency of insulin, with hyperglycemia being hallmark medical finding DM can occur as either an early onset form (type 1) or a gradual-onset form (type 2) In T1DM, insulin-producing β cells of pancreas are destroyed or insufficiently active, and patients require lifelong treatment with exogenous insulin In T2DM, adequate control of disease may be achieved by means of diet and exercise if these methods fail, patients take oral hypoglycemic agents, which cause o lower plasma glucose levels o improve insulin resistance, and o reduce long-term complications (macrovascular and microvascular problems such as neuropathy, nephropathy, retinopathy and CVD) Marc Imhotep Cray, MD
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Basic Concepts (10) For type 1 DM Insulin is sole treatment and is sometimes also used for type 2 DM For type 2 DM, drugs include sulfonylureas, which stimulate insulin secretion from pancreatic β cells metformin, a biguanide that decreases blood glucose levels by reducing hepatic glucose production and glycogen metabolism in liver and improving insulin resistance meglitinides, which increase insulin secretion from pancreatic β cells α-glucosidase inhibitors, which delay carbohydrate digestion and glucose absorption and thiazolidinedione (TZD) derivatives (eg, rosiglitazone and pioglitazone), which reduce insulin resistance Marc Imhotep Cray, MD
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Concept of negative feedback What is a feedback loop? Hormone synthesis and release are governed at multiple levels Hormone synthesis/release from an organ of interest typically involves regulation by a pituitary hormone, which itself is regulated by a hypothalamic hormone This general pathway structure is commonly referred to as a hypothalamic-pituitary-(organ) axis e.g., HPO axis refers to ovary, HPA axis refers to adrenal gland Negative feedback occurs when a product downstream of an axis inhibits production of a reactant by which it is regulated for example, thyroid hormone inhibition of thyroid-stimulating hormone (TSH) These relationships are often depicted using feedback loops (next 2 slide) Marc Imhotep Cray, MD
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Regulation of hormone synthesis and secretion ď ą To best understand endocrine pharmacology it is essential understand the negative feedback principle of the hypothalamic/pituitary/ target organ axis
ď ą A negative feedback mechanism is an example of a negative effect Solid lines = positive effect Dashed lines = negative effect Marc Imhotep Cray, MD
Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010
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Thyroid hormone feedback loop
Marc Imhotep Cray, MD
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
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Hormones of the hypothalamic-pituitary axis
Marc Imhotep Cray, MD
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
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Hormone
Site of Release
Action
Stimulators
Inhibitors
PRF
Modified from: Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009
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Relationships Among Hypothalamic, Pituitary, and Target Gland Hormones HYPOTHALAMIC
PITUITARY
TARGET ORGAN
TARGET ORGAN HORMONES
GHRH (+), SRIH (–), CRH (+)
GH (+)
Liver
Somatomedins
ACTH (+)
Adrenal cortex
Glucocorticoids Mineralocorticoids Androgens
TRH (+)
TSH (+)
Thyroid
T4, T3
GnRH or LHRH (+)
FSH (+), LH (+)
Gonads
Estrogen Progesterone Testosterone
Dopamine (–), PRH (+)
Prolactin (+)
Breast
—
Redrawn after: Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010
+, stimulant; –, inhibitor; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, folliclestimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropinreleasing hormone; LHRH, luteinizing hormone-releasing hormone; LH, luteinizing hormone; PRH, prolactin-releasing hormone; SRIH, somatotropin-releasing inhibiting hormone; TRH, thyrotropin releasing hormone; TSH, thyroidMarc Imhotephormone. Cray, MD stimulating
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Hormones that Integrate the HypothalamicPituitary-Endocrine Axis
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011
Marc Imhotep Cray, MD
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THE END
See next slide for further study. Marc Imhotep Cray, MD
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Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, MD
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