Hormones Part 1

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arachidonic acid derivatives that are derived from phospholipids

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eicosanoids

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cholesterol derivatives

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steroids

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function of pituitary gland

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receives input from hypothalamus and releases appropriate homrones into systemic circulation

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2 major mechanisms for hormone inactivation

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1- inactivation by enzymes
2- inactivation via removal from receptor area

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3 main mechanisms for regulation of hormone synthesis

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negative control, positive control, feedback inhibition

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tumor formation commonly results in ______ of a particular hormone

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overproduction

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Autoimmune disorders or genetic defects often cause ______ of a particular hormone

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underproduction

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Caused by a lack of functional receptors due to genetic defects, autoimmune disorders or overstimulation and downregulation of receptors

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target cell insensitivity

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AVP/ADH--function?

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stimulates water reabsorption in principal cells of collecting ducts and constriction of arterioles

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AVP/ADH--origin?

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posterior pituitary

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Oxytocin--function?

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stimulates milk ejection from breasts and causes uterine contractions (child birth and copulation)

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Oxytocin--origin?

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posterior pituitary

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Thyroid stimulating hormone (TSH): origin and function

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anterior pituitary; stimulates synthesis and secretion of thyroid hormones

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Follicle-stimulating hormone (FSH)

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anterior pituitary; stimulates sperm maturation in Sertoli cells and follicular development and estrogen syntesis in ovaries.

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Luteinizing hormone (LH)

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anterior pituitary; stimulates testosterone synthesis in Leydig cells, stimulates ovulation, formation of corpus luteum, estrogen and progesterone synthesis in ovaries

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Growth hormone: origin and function

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anterior pituitary; stimulates protein synthesis and overall growth

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Prolactin: origin and function

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anterior pituitary; stimulates milk production and secretion in breast

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Adrenocorticotropic-hormone (ACTH): origin and function

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anterior pituitary; stimulates synthesis and secretion of adrenal cortical hormones (cortisol, androgens, aldosterone)

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Melanocyte-stimulating hormone (MSH): origin and function

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anterior pituitary; stimulates melanin synthesis

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Thyrotropin-releasing hormong (TRH): origin and function

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hypothalamus; simulates secretion of TSH and prolactin

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Corticotropin-releasing hormone (CRH): origin and function

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hypothalamus; stimulates secretion of ACTH

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Gonadotropin-releasing hormone (GnRH): origin and function

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hypothalamus; stimulates secretion of FSH and LH

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Somatostatin or Somatotropin release-inhibiting homrone (SRIF): origin and function

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hypothalamus; inhibits secretion of growth hormone

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Dopamine or Prolactin-ihibiting factor (PIF): origin and function

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hypothalamus; inhibits secretion of prolactin

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Growth hormone-releasing hormone (GHRH)

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hypothalamus; stimultes secretion of GH

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Calcitonin

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thyroid; decreases serum calcium

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increases serum calcium conc

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parathyroid hormone

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stimulates estrogen and progesterone synthesis in corpus luteum of early pregnancy

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hCG (human chorinic gonadotropin)

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has GH-like and prolactin-like actions during pregnancy

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human placental lactogen (hPL) or human chorionic somatomammotropin

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catalyzes conversion of angiotensinogen to angiotensis I

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renin; released by kidney

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contains a 15-25 residue signal sequence of mostly hydrophobic amino acids at its N-terminus that allows entry into the ER

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pre-prohormone

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are peptide hormones stored in secretory granules?

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yes: they are packaged by the TGN into immature secretory granules along with their processing enzymes and other required proteins

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An acidic environment in the immature secretory granules is required for what process?

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cleavage on carboxy side of paired basic residues of the prohormone (i.e., lysine or arginine)

Front 34

What process follows cleavage at paired basic residues?

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peptide hormones are amidated, which makes them more biologically active and helps preserve their half-life once secreted

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enzyme that amidates prohormones

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PAM (peptidylGlydie-a-amidating monooxygenase )

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prohormone from which ACTH and beta-LPH are made

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pro-opiomelanocortin (POMC)

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what is responsible for the differential processing of POMC?

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enzyme location; conditions (stress, etc.)

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inhibits release of CRH at hypothalamus and release of ACTH at anterior pituitary(via feedback inhibition)

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cortisol

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inhibits release of ACTH from anterior pituitary via negative inhibition

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dopamine

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In episodic/circadian secretion, which is secreted first: cortisol or ACTH?

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ACTH--ACTH causes release of cortisol which then directly inhibits ATCH production and release from the pituitary

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Cushing's Disease or Syndrome: caused by ACTH secreting tumors of pituitary

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Disease

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Adenoma of adrenal cortex causes release of excess cortisol due to overproduction...what disease?

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Cushing's Syndrome

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ketoconazole and metyrapone are used to treat what disease?

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Cushing's Syndrome

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treatment for Cushing's disease?

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surgical removal o ACTH secreting tumor

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The following symptoms describe what disease: polyuria, polydipsia, dehydration, weakness, mental retardation if not treated

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Diabetes insipidus

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What type of Diabetes Insipidus is caused by a loss of functionality of AVP receptor in the kidney (usually mutations)

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Nephrogenic---treat with ibuprofen

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What type of Diabetes Insipidus develops during pregnancy and dissappears 4-6 weeks after delivery?

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Gestational--treat with desmopressin (synthetic AVP) and time

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What type of Diabetes Insipidus is caused by suppression of vasopressin by excessive intake of fluids?

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Dipsogenic--treat by decreasing water intake

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What type of Diabetes Insipidus is characterized by a defect int he secretion of AVP from the posterior pituitary, is inherited (via x-linked or autosomal dominant)?

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Neurogenic--treat with desmopressin (synthetic AVP)

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Enzyme that iodinates thyroglobin

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thyroidal peroxidase (TPO)

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synthesized in thyroid follicular cells stored as a part of thryoglobin

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MIT and DIT (monoiodotyrosine and diiodotyrosine)

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where is TPO located?

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apical border of thyroid acinar cell

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coupling reactions of MIT and DIT form what 2 hormones

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T3 and T4

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stored in colloidal space where it is iodinated

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thryoglobulin (TGb)

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what stimulates endocytosis of TGb at apical membrane of acinar cell?

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binding of TSH to receptor on basal membrane

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What happens in endosomes following endocytosis of TGb?

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proteases from lysosomes cleave peptide bonds to form T3 and T4 that are released into circulation and MIT and DIT which are recycled

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how are MIT and DIT recycled?

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deiodinase breaks MIT and DIT down into tyrosine and iodine

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90% T4 and 10% T3 but T3 is more active---why 90/10?

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major pathway of thyroid metabolism is sequential deiodination, thus 80% of circulating T3 is dervied from T4

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major site of T3 and T4 degradation

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liver (minor sites are kidney and other tissues)

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thyroid hormones can be conjugated with sulfaces and glucuronides and excreted into bile so that they can undergo what process?

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enterhepatic circulation

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thyroid hormones are primarily eliminated via what organ

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kidneys--but some conjugated hormone is eliminated in feces

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T3 and T4 exhibit feedback inhibition...affects secretion of what?

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TRH, TSH

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What disease: lowered basal metabolic rate, diastolic hypertension, goiter

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hypothyroidism (insufficient T3/T4)

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What disease: increased metabolic rate, exophthalmos, goiter

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hyperthyroidism (autoimmune---Anitbodies to TSH receptor)

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Levothyroxine treats what disease?

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hypothyroidism

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Treatment options for hyperthyroidism

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surgical resection/ 131-Iodide to destroy the hyperfunctioning cell population

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When thryroid failure results in decreased T3/T4, what is the response of the pituitary?

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increased secretion of TSH--goiter forms because the only way to keep up/increase production of T3/T4 is to enlarge

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Antibodies to TSH receptor cause its activation and body thinks it needs more T3/T4 even though it may not. What results from this?

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Goiter--gland increases size to keep up production of T3/T4

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common characteristics of Serotonin, Melatonin and Catecholamines

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derived from amino acids, small molecules, neurotransmitters

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major elements in response to severe stress

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catecholamines

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increases HR and SV, dilates pupils, constricts skin and gut arterioles and dilates arterioles in leg muscles, increases blood sugar, increases lipolysis, suppresses immune system

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epinephrine (and norepinephrine)

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dopamine

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neurotransmitter as well as hormone that inhibits release of prolactin

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T or F: catecholamines can cross the blood-brain barrier

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Falso, must be synthesized in CNS...L-DOPA can cross though

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synthesis location of Epi, NE, and Dopamine

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Epi-adrenal medulla
NE-mainly in sympathetic nerves, also adrenal medulla and CNS
Dopamine- CNS

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Precursor for all catecholamines

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Tyrosine

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rate limiting steop for catecholamine synthesis

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tyrosine hydroxylase, which is activated by a cAMP-dependent protein kinase

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Type of secretion for catecholamines: constituative or regulated

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regulated (secretory granules)

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2 regulation methods for catecholamines

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degradation by MAO and re-uptake

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path from tyrosine to epinephrine

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Tyrosine→DOPA→Dopamine→NE→Epi

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works with MAO to metabolize catetcholamines

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catechol-O-methyltransferase (COMT)--methylates hydroxyl group

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Disease? : slight male predominance, can be caused by infection, toxins, drugs, association with other neurodegenerative disorders, trauma, metabolic disorders and multiple infarct...present with tremors

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Parkinson's Disease

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Carbidopa treats what?

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peripheral decarboxylase inhibitor that treats Parkinson's

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active ingredient of what treatment for Parkinson's is precursor to dopamine?

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levodopa

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Dopamine agonists used as adjunct to L-Dopa

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Bromocriptine, Pergolide

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Disease: excess production of catecholamines resultig in hypertension and tachycardia

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Pheochromocytomas--tumors of adreanal medulla or sympathetic ganglia

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Treatment for Pheochromocytomas

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surgical resection of tumos, radiation thereapy, chemotherapy

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Plays a role in regulation of mood, sleep, emesis, sexuality and appetite; plays a part in depression, migraines, bipolar disorder, anxiety

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Serotonin
other roles: liver regeneration, acts as mitogen throughout body, vasocontrictor in blood serum

Front 88

Melatonin is regulated by dark/light and thus regualtes sleep/wake cycles. When is it released/suppressed?

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Released during darkness, suppressed by daylight

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What is melatonin used for clinically?

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inducing sleep, preventing jet lag (works best at times wen it is not being produced in high quanitity)

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Synthesis location of Serotonin and Melatonin

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Pineal gland
-Serotonin also secreted by small intestine

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Precursor to serotonin and melatonin? rate limiting step?

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Tryptophan; tryptophan hydroxylase

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Enzyme responsible for conversion of N-acetylserotonin to melatonin?

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hydroxyindol-O-methyl transferase (HIOMT)

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Serotonin and Melatonin: constituative or regulated secretion?

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regulated

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Degradation of Serotonin/Melatonin

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both broken down by MAO
5HT removed by transport protein--must be removed for it will continue to elicit response

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What Disease: depressed mood caused by chemical imbalance

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Depression

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Treatment for depression?

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inhibit MAO or prevent removal of NTs from synaptic cleft--SSRIs: serotonin specific re-uptake inhibitors (fluoxetine and paroxetine)

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generic names for Prozac and Paxil and potentian risks

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Prozac: Fluoxetine--potential for low birth weight, premature labor and heart defects for fetus
Paxil: Paroxetine--potential for lung defects

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What disease? genetic, defective absortption of tryptophan, symptoms include photosensitive dermatitis, intermittent neurological symptoms, and blue diaper syndrome (indicanuria)

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Hartnup's Disease--autosomal recessive

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Treatment for Hartnup's syndrome?

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high protein diet with di-peptide tryptophan (di-peptides can be absorbed via di-peptide transporter)

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H-dependent ACh transporter in synaptic vesicles is responsible for what?

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concentration of ACh

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enzymes that process ACh

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CHAT--synthesis
AChE--degradation

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Degradation of ACh

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hydrolysis by AChE into choline and acetate--choline is taken up by nerve terminal and ACh is resynthesized by CHAT then concentrated into vesicles

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What disease? symptoms of double vision, ptosis, difficulting swallowing, generalized weakness caused by anitbodies against ACh receptors

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myasthenia gravis

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Treatment for myastenia gravis?

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Pyridostigmine--AChE inhibitor

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Organophosphates inhibit AChE resulting in what?

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hypercholinergic effect due to buildup of ACh in synapses

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Treatment for hypercholingeric effects of chemical exposure?

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atropine, diazepam, pralidoxime