Human Physiology

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Chapter 11
Endocrine Glands - Secretion Action of Hormones
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• Chapter 11 Outline
• Overview
• Chemical Classification of Hormones
• Hormonal Actions Interactions
• Mechanisms of Hormone Action
• Pituitary Gland
• Adrenal Gland
• Thyroid Gland
• Islets of Langerhans
• Miscellaneous Glands Hormone
• Autocrine Paracrine Regulation

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Overview
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Endocrine Glands

• Are ductless secrete hormones into bloodstream
• Hormones go to target cells that contain receptor
  proteins for it
• Neurohormones are secreted into blood by
  specialized neurons
• Hormones affect metabolism of targets

Fig 11.1
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Chemical Classification of Hormones
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Chemical Classification of Hormones

• Amine hormones are derived from tyrosine or
  tryptophan
• Include NE, Epi, thyroxine, melatonin
• Polypeptide/protein hormones are chains of amino
  acids
• Include ADH, GH, insulin, oxytocin, glucagon,
  ACTH, PTH
• Glycoproteins include LH, FSH, TSH
• Steroids are lipids derived from cholesterol
• Include testosterone, estrogen, progesterone
  cortisol

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Chemical Classification of Hormones continued

• Steroid thyroid hormones are lipids
• Can diffuse into target cells
• The 2 major thyroid hormones are shown in Fig
  11.3

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Prohormones Prehormones

• Prohormones are precursors of hormones
• E.g. proinsulin
• Prehormones are precursors of prohormones
• E.g. preproinsulin
• Some hormones are inactive until activated by
  target cells
• E.g. thyroxine (T4) is inactive until converted
  to T3 in target cells

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Hormonal Actions Interactions
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Common Aspects of Neural Endocrine Regulation

• Both NS endocrine system use chemicals to
  communicate
• Difference between NTs hormones is transport in
  blood more diversity of effects in hormone
  targets
• Some chemicals are used as hormones NTs
• Targets for both NTs hormones must have
  specific receptor proteins
• Must be way to rapidly inactivate both

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Hormone Interactions

• A tissue usually responds to of hormones
• 2 hormones are synergistic if work together to
  produce an effect
• Produce a larger effect together than individual
  effects added together
• A hormone has permissive effect if it enhances
  responsiveness of a target organ to 2nd hormone
• If action of 1 hormone inhibits effect of
  another, it is antagonistic

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Hormone Levels Tissue Responses

• Half-life is time required for blood level to be
  reduced by half
• Ranges from mins to hrs for most (days for
  thyroid hormones)
• Normal tissue responses are produced only when
  hormones are in physiological range
• High (pharmacological) doses can cause of side
  effects
• Probably by binding to receptors of other
  hormones

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Hormone Action

• Hormones alter target cell activity by one of two
  mechanisms
• Second messengers involving
• Regulatory G proteins
• Amino acidbased hormones
• Direct gene activation involving steroid hormones
• The precise response depends on the type of the
  target cell

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Mechanism of Hormone Action

• Hormones produce one or more of the following
  cellular changes in target cells
• Alter plasma membrane permeability
• Stimulate protein synthesis
• Activate or deactivate enzyme systems
• Induce secretory activity
• Stimulate mitosis

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Hormone Levels Tissue Responses continued

• Priming effect (upregulation) occurs when a
  hormone induces more of its own receptors in
  target cells
• Results in greater response in target cell
• Desensitization (downregulation) occurs after
  long exposure to high levels of polypeptide
  hormone
• Subsequent exposure to this hormone produces a
  lesser response
• Due to decrease in of receptors on targets
• Most peptide hormones have pulsatile secretion
  which prevents downregulation

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Mechanisms of Hormone Action
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Mechanisms of Hormone Action

• Target cell receptors show specificity, high
  affinity, low capacity for a hormone
• Lipid hormones have receptors in target's
  cytoplasm /or nucleus because can diffuse thru
  plasma membrane
• Receptors for water-solubles are on surface of
  target cell

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Hormones That Bind to Nuclear Receptor Proteins

• Lipid hormones travel in blood attached to
  carrier proteins
• They dissociate from carriers to pass thru plasma
  membrane of target
• Receptors are called nuclear hormone receptors

Fig 11.4
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Nuclear Hormone Receptors

• Serve as transcription factors when bound to
  hormone ligands
• Activate transcription
• Constitute a "superfamily" composed of steroid
  family thyroid hormone family (which includes
  vitamin D retinoic acid)

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Nuclear Hormone Receptors

• Have ligand (hormone)-binding DNA-binding
  domains
• Binds hormone translocates to nucleus
• Binds to hormone-response element (HRE) on DNA
  located adjacent to target gene

Fig 11.5
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Steroid Hormones

• Steroid hormones and thyroid hormone diffuse
  easily into their target cells
• Once inside, they bind and activate a specific
  intracellular receptor
• The hormone-receptor complex travels to the
  nucleus and binds a DNA-associated receptor
  protein
• This interaction prompts DNA transcription to
  produce mRNA
• The mRNA is translated into proteins, which bring
  about a cellular effect

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Steroid Hormones
Figure 16..3
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Target Cell Specificity

• Hormones circulate to all tissues but only
  activate cells referred to as target cells
• Target cells must have specific receptors to
  which the hormone binds
• These receptors may be intracellular or located
  on the plasma membrane
• Examples of hormone activity
• ACTH receptors are only found on certain cells of
  the adrenal cortex
• Thyroxin receptors are found on nearly all cells
  of the body

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Target Cell Activation

• Target cell activation depends on three factors
• Blood levels of the hormone
• Relative number of receptors on the target cell
• The affinity of those receptors for the hormone
• Up-regulation target cells form more receptors
  in response to the hormone
• Down-regulation target cells lose receptors in
  response to the hormone

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Mechanisms of Steroid Hormones

• HRE consists of 2 half-sites
• 2 ligand-bound receptors have to bind to each HRE
  (dimerization)
• This stimulates transcription of target gene

Fig 11.5
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Mechanism of Thyroid Hormone Action

• Thyroid secretes 90 T4 (thyroxine) 10 T3
• 99.96 of T4 in blood is bound to carrier protein
  (thyroid binding globulin - TBG)
• Only free can enter cells, so bound is reservoir
• T4 converted to T3 inside cell
• T3 binds to receptor protein located in nucleus

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Mechanism of Thyroid Hormone Actioncontinued

• T3 receptor bind to 1 half-site
• Other half-site binds retinoic acid
• Two partners form heterodimer that activates HRE
• Stimulates transcription of target gene

Fig 11.7
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Hormones That Use 2nd Messengers

• Water soluble hormones use cell surface receptors
  because cannot pass through plasma membrane
• Actions are mediated by 2nd messengers
• Hormone is extracellular signal 2nd messenger
  carries signal from receptor to inside of cell

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Amino Acid-Based Hormone Action cAMP Second
Messenger

• Hormone (first messenger) binds to its receptor,
  which then binds to a G protein
• The G protein is then activated as it binds GTP,
  displacing GDP
• Activated G protein activates the effector enzyme
  adenylate cyclase
• Adenylate cyclase generates cAMP (second
  messenger) from ATP
• cAMP activates protein kinases, which then cause
  cellular effects

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Adenylate Cyclase-cAMP

• Mediates effects of many polypeptide
  glycoprotein hormones
• Hormone binds to receptor causing dissociation of
  a G-protein subunit

Fig 11.8
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Adenylate Cyclase-cAMP continued

• G-protein subunit binds to activates adenylate
  cyclase
• Which converts ATP into cAMP
• cAMP attaches to inhibitory subunit of protein
  kinase

Fig 11.8
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Adenylate Cyclase-cAMP continued

• Inhibitory subunit dissociates, activating
  protein kinase
• Which phosphorylates enzymes that produce
  hormones effects
• cAMP inactivated by phosphodiesterase

Fig 11.8
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Amino Acid-Based Hormone Action cAMP Second
Messenger
Figure 16.2a
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Phospholipase-C-Ca2

• Serves as 2nd messenger system for some hormones
• Hormone binds to surface receptor, activates
  G-protein, which activates phospholipase C

Fig 11.9
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Phospholipase-C-Ca2

• Phospholipase C splits a membrane phospholipid
  into 2nd messengers IP3 DAG
• IP3 diffuses through cytoplasm to ER
• Causing Ca2 channels to open

Fig 11.9
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Phospholipase-C-Ca2 continued

• Ca2 diffuses into cytoplasm binds to
  activates calmodulin
• Ca2-Calmodulin activates protein kinases which
  phosphorylate enzymes that produce hormone's
  effects

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Epi Can Act Via Two 2nd Messengers
Fig 11.10
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Tyrosine Kinase 2nd Messenger System

• Is used by insulin many growth factors to cause
  cellular effects
• Surface receptor is tyrosine kinase
• Consists of 2 units that form active dimer when
  insulin binds

Fig 11.11
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Tyrosine Kinase 2nd Messenger System

• Activated tyrosine kinase phosphorylates
  signaling molecules that induce hormone/growth
  factor effects

Fig 11.11
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Hormone Concentrations in the Blood

• Hormones circulate in the blood in two forms
  free or bound
• Steroids and thyroid hormone are attached to
  plasma proteins
• All others are unencumbered

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Hormone Concentrations in the Blood

• Concentrations of circulating hormone reflect
• Rate of release
• Speed of inactivation and removal from the body
• Hormones are removed from the blood by
• Degrading enzymes
• The kidneys
• Liver enzyme systems

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Interaction of Hormones at Target Cells

• Three types of hormone interaction
• Permissiveness one hormone cannot exert its
  effects without another hormone being present
• Synergism more than one hormone produces the
  same effects on a target cell
• Antagonism one or more hormones opposes the
  action of another hormone

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Control of Hormone Release

• Blood levels of hormones
• Are controlled by negative feedback systems
• Vary only within a narrow desirable range
• Hormones are synthesized and released in response
  to
• Humoral stimuli
• Neural stimuli
• Hormonal stimuli

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Humoral Stimuli

• Humoral stimuli secretion of hormones in direct
  response to changing blood levels of ions and
  nutrients
• Example concentration of calcium ions in the
  blood
• Declining blood Ca2 concentration stimulates the
  parathyroid glands to secrete PTH (parathyroid
  hormone)
• PTH causes Ca2 concentrations to rise and the
  stimulus is removed

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Humoral Stimuli
Figure 16.4a
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Neural Stimuli

• Neural stimuli nerve fibers stimulate hormone
  release
• Preganglionic sympathetic nervous system (SNS)
  fibers stimulate the adrenal medulla to secrete
  catecholamines

Figure 16.4b
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Hormonal Stimuli

• Hormonal stimuli release of hormones in
  response to hormones produced by other endocrine
  organs
• The hypothalamic hormones stimulate the anterior
  pituitary
• In turn, pituitary hormones stimulate targets to
  secrete still more hormones

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Hormonal Stimuli
Figure 16.4c
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Nervous System Modulation

• The nervous system modifies the stimulation of
  endocrine glands and their negative feedback
  mechanisms
• The nervous system can override normal endocrine
  controls
• For example, control of blood glucose levels
• Normally the endocrine system maintains blood
  glucose
• Under stress, the body needs more glucose
• The hypothalamus and the sympathetic nervous
  system are activated to supply ample glucose

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Pituitary Gland
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Pituitary Gland

• Pituitary gland is located beneath hypothalamus
  at base of forebrain

Fig 8.16
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Pituitary Gland continued

• Is structurally functionally divided into
  anterior posterior lobes
• Hangs below hypothalamus by infundibulum
• Anterior produces own hormones
• Controlled by hypothalamus
• Posterior stores releases hormones made in
  hypothalamus

Fig 11.12
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Anterior Pituitary

• Secretes 6 trophic hormones that maintain size of
  targets
• High blood levels cause target to hypertrophy
• Low levels cause atrophy

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Anterior Pituitary continued

• Growth hormone (GH) promotes growth, protein
  synthesis, movement of amino acids into cells
• Thyroid stimulating hormone (TSH) stimulates
  thyroid to produce secrete T4 T3
• Adrenocorticotrophic hormone (ACTH) stimulates
  adrenal cortex to secrete cortisol, aldosterone
• Follicle stimulating hormone (FSH) stimulates
  growth of ovarian follicles sperm production
• Luteinizing hormone (LH) causes ovulation
  secretion of testosterone in testes
• Prolactin (PRL) stimulates milk production by
  mammary glands

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Anterior Pituitary continued

• Release of A. Pit. hormones is controlled by
  hypothalamic releasing inhibiting factors by
  feedback from levels of target gland hormones

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Anterior Pituitary continued

• Releasing inhibiting hormones from hypothalamus
  are released from axon endings into capillary bed
  in median eminence
• Carried by hypothalamo-hypophyseal portal system
  directly to another capillary bed in A. Pit.
• Diffuse into A. Pit. regulate secretion of its
  hormones

Fig 11.15
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Feedback Control of Anterior Pituitary

• Involves short feedback loop in which retrograde
  flow of blood hormones from A. Pit. to
  hypothalamus inhibits secretion of releasing
  hormone
• Involves negative feedback of target gland
  hormones
• during menstrual cycle, estrogen stimulates LH
  surge by positive feedback

Fig 11.17
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Higher Brain Function Anterior Pituitary
Secretion

• Hypothalamus receives input from higher brain
  centers that can affect A. Pit. secretion
• E.g. psychological stress affects circadian
  rhythms, menstrual cycle, adrenal hormones

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Posterior Pituitary

• Stores releases 2 hormones produced in
  hypothalamus
• Antidiuretic hormone (ADH/vasopressin) which
  promotes H20 conservation by kidneys
• Oxytocin which stimulates contractions of uterus
  during parturition
• contractions of mammary gland alveoli for
  milk-ejection reflex

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Hypothalamic Control of Posterior Pituitary

• Supraoptic nuclei of hypothalamus produce ADH
• Paraventricular nuclei produce oxytocin
• Both transported along hypothalamo-hypophyseal
  tract to posterior pituitary
• Release controlled in hypothalamus by
  neuroendocrine reflexes

Fig 11.13
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Adrenal Gland
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Adrenal Glands

• Sit on top of kidneys
• Each consists of outer cortex inner medulla
• 2 arise differently during development

Fig 11.18
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Adrenal Glands

• Medulla synthesizes secretes 80 Epi 20 NE
• Controlled by sympathetic
• Cortex is controlled by ACTH secretes
• Cortisol which inhibits glucose utilization
  stimulates gluconeogenesis
• Aldosterone which stimulate kidneys to reabsorb
  Na and secrete K
• some supplementary sex steroids

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Adrenal Cortex
Fig 11.19
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Adrenal Medulla

• Hormonal effects of Epi last 10X longer than NE
• Innervated by preganglionic Symp fibers
• Activated during "fight or flight" response
• Causes
• Increased respiratory rate
• Increased HR cardiac output
• General vasoconstriction which increases venous
  return
• Glycogenolysis lipolysis

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Stress the Adrenal Gland

• Stress induces a non-specific response called
  general adaptation syndrome (GAS)
• Causes ACTH cortisol release
• Often affects physiology negatively

Fig 11.20
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Stress and the Adrenal Gland
Figure 16.15
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Thyroid Gland
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Thyroid Gland

• Is located just below the larynx
• Secretes T4 T3 which set BMR are needed for
  growth, development

Fig 11.21
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Thyroid Gland

• Consists of microscopic thyroid follicles
• Outer layer is follicle cells that synthesize T4
• Interior filled with colloid, a protein-rich
  fluid

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Production of Thyroid Hormones

• Iodide (I-) in blood is actively transported into
  follicles secreted into colloid
• Where it is oxidized to iodine (I2) attached to
  tyrosines of thyroglobulin
• A large storage molecule for T4 T3
• TSH stimulates hydrolysis of T4 T3s from
  thyroglobulin then secretion

Fig 11.23
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Thyroid Hormone

• Thyroid hormone the bodys major metabolic
  hormone
• Consists of two closely related iodine-containing
  compounds
• T4 thyroxine has two tyrosine molecules plus
  four bound iodine atoms
• T3 triiodothyronine has two tyrosines with
  three bound iodine atoms

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Effects of Thyroid Hormone

• TH is concerned with
• Glucose oxidation
• Increasing metabolic rate
• Heat production
• TH plays a role in
• Maintaining blood pressure
• Regulating tissue growth
• Developing skeletal and nervous systems
• Maturation and reproductive capabilities

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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
• Mechanisms of activity are similar to steroids
• Regulation is by negative feedback
• Hypothalamic thyrotropin-releasing hormone (TRH)
  can overcome the negative feedback

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Diseases of the Thyroid - Goiter

• In absence of sufficient dietary iodide, T4 T3
  cannot be made levels are low
• Low T4 T3 dont provide negative feedback TSH
  levels go up
• Because TSH is a trophic hormone, thyroid gland
  grows
• Resulting in a goiter

Fig 11.25
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Diseases of the Thyroid - Hypothyroidism

• People with inadequate T4 T3 levels are
  hypothyroid
• Have low BMR, weight gain, lethargy, cold
  intolerance
• myxedema puffy face, hands, feet
• During fetal development hypothyroidism can cause
  cretenism (severe mental retardation)

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Diseases of the Thyroid - Hyperthyroidism

• Goiters are also produced by Grave's disease
• Autoimmune disease where antibodies act like TSH
  stimulate thyroid gland to grow oversecrete
  hyperthyroidism
• Characterized by exopthalmos, weight loss, heat
  intolerance, irritability, high BMR

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Parathyroid Glands

• Are 4 glands embedded in lateral lobes of thyroid
  gland
• Secrete Parathyroid hormone (PTH)
• Most important hormone for control of blood Ca2
  levels

Fig 11.28
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Parathyroid Hormone

• Release stimulated by decreased blood Ca2
• Acts on bones, kidney, intestines to increase
  blood Ca2 levels

Fig 11.29
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Islets of Langerhans
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Islets of Langerhans

• Are scattered clusters of endocrine cells in
  pancreas
• Contain alpha beta cells

Fig 11.30
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Islets of Langerhans continued

• Alphas secrete glucagon in response to low blood
  glucose
• Stimulates glycogenolysis lipolysis
• Increases blood glucose

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Islets of Langerhans continued

• Betas secrete insulin in response to low blood
  glucose
• Promotes entry of glucose into cells
• conversion of glucose into glycogen fat
• Decreases blood glucose

Fig 11.31
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Miscellaneous Glands Hormones
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Pineal Gland

• Is located in basal forebrain near thalamus
• Secretes melatonin in response to activity of
  suprachiasmatic nucleus (SCN) of hypothalamus

Fig 11.32
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Pineal Gland continued

• SCN is primary timing center for circadian
  rhythms
• Reset by daily light/dark changes
• Melatonin is involved in aligning physiology with
  sleep/wake cycle seasons
• Secreted at night is inhibited by light
• Inhibits GnRH (antigonadotropic) in many animals

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Thymus

• Is located around trachea below thyroid
• Produces T cells of immune system hormones that
  stimulate them

Fig 11.33
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Sex Reproductive Hormones

• Gonads (testes ovaries) secrete steroid
  hormones testosterone, estrogen, progesterone
• Placenta secretes estrogen, progesterone, hCG,
  and somatomammotropin

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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

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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

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Autocrine Paracrine Regulation
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Autocrine Paracrine Regulation

• Autocrine regulators are produced act within
  same tissue of an organ
• All autocrines control gene expression in target
  cells
• Paracrine regulators are autocrines that are
  produced within one tissue act on different
  tissue in same organ.
• Autocrines paracrines include
• Cytokines (lymphokines, interleukins)
• Growth factors (promote growth cell division)
• Neutrophins (provides trophic support for normal
  regenerating neurons)

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Prostaglandins (PGs)

• Are produced in almost every organ
• Belong to eicosanoid family -- all derived from
  arachidonic acid of plasma membrane

Fig 11.34
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Prostaglandins (PGs) continued

• Have wide variety of functions
• Different PGs may exert antagonistic effects in
  tissues
• Some promote smooth muscle contraction some
  relaxation
• Some promote clotting some inhibit
• Promotes inflammatory process of immune system
• Plays role in ovulation
• Inhibits gastric secretion in digestive system

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Prostaglandins (PGs) continued

• Cyclooxygenase (COX) 1 2 are involved in PG
  synthesis (Fig 11.34)
• Are targets of a number of inhibitory
  non-steroidal anti-inflammatory drugs (NSAIDs)
• Aspirin, indomethacin, ibuprofen inhibit both COX
  1 2 thereby producing side effects
• Celebrex Vioxx only inhibit COX 2 thus have
  few side effects

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