Prof.%20Omar%20Al-Attas

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Biochemical EndocrinologyBCH 560

• Prof. Omar Al-Attas
• King Saud University
• Department of Biochemistry
• College of Science

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• Endocrinology is the capacity of specialized
  tissues to function in integral fashion as
  components of intact organism which is made
  possible in large by two control mechanism.

Nervous system Neurotransmitters i.e.
Acetylcholine, Dopamine, Serotonin, Gamma
Aminobutyric Acid (GABA), Glutamate, Epinephrine
and Norepinephrine, Endorphins
Endocrine system Hormones i.e. ADH, ACTH,
Prolactin, Calcitonin ,Parathyroid, Renin,
Insulin, Glucagon, CCK, Resistin, Leptinetc
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Endocrine versus Nervous Systems

• Major communication systems in the body
• Integrate stimuli and responses to changes in
  external and internal environment
• Both are crucial to coordinated functions of
  highly differentiated cells, tissues and organs
• Unlike the nervous system, the endocrine system
  is anatomically discontinuous.

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Cont

• The endocrine system broadcasts its hormonal
  messages to essentially all cells by secretion
  into blood and extracellular fluid.
• Like a radio broadcast, it requires a receiver to
  get the message
• in the case of endocrine messages, cells must
  bear a receptor for the hormone being broadcast
  in order to respond.

• The nervous system exerts point-to-point control
  through nerves, similar to sending messages by
  conventional telephone.
• Nervous control is electrical in nature and fast.

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• Endocrinology traditionally defined as the action
  of hormones and the organs in which the hormones
  are formed.
• It is About
• The study of anatomy and physiological function
  of the major endocrine organs.
• The secretory products of these organs.
• The mechanism of hormone action.
• The clinical manifestation of hormone action

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• The interlocking nature of the nervous and
  endocrine systems is that there is no sharp
  distinction between the two systems.

Nervous System
Endocrine System
Regulated Organs or Tissue
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Endocrine Gland

• Their products are secreted directly and
  internally into the blood stream which do not
  utilize ducts. These ductless glands were termed
  Endocrine.

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The Classic Gland
Cont
Thyroid and Parathyroid
Adrenals
Placenta
Male and Female Gonads
Pancreatic islets
Prostaglandin
Pituitary
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Types of Hormones

• Products of the ductless gland (Endocrine
  Hormones)
• Work at a relatively short range (Telecrine)
• Work at a nearby hormones (Paracrine)- cells
  secret
• substances that diffuse into the extracellular
• fluid and affect neighboring cells.

Endocrine and Telecrine glands or specialized
cells release hormones into the circulating blood
that influence the function of cells at another
location in the body.
At present, there are about 50 known hormones
such as protein, small peptide and steroids.
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Mechanism of Action of Hormone

• Hormone are chemical messengers synthesized by
  organism that initiate
• biological responses by binding with high
  affinity and specificity to target
• cell receptors within the same individual.
• They are
• Endogenous substance
• High affinity and specificity of binding to
  specific receptors on target cells
• Initiates biological response

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Amine Hormone

• Derivatives of tyrosine
• Catecholamines (epinephrine, dopamine)
  Catecholamines are both neurohormones and
  neurotransmitters.
• These include epinephrine, and norepinephrine
• Epinephrine and norepinephrine are produced by
  the adrenal medulla both are water soluble
• Secreted like peptide hormones
• Thyroid Hormone (dipeptides) are basically a
  "double" tyrosine with the critical incorporation
  of 3 or 4 iodine atoms.
• Thyroid hormone is produced by the thyroid gland
  and is lipid soluble
• Thyroid hormones are produced by modification of
  a tyrosine residue contained in thyroglobulin,
  post-translationally modified to bind iodine,
  then proteolytically cleaved and released as T4
  and T3. T3 and T4 then bind to thyroxin binding
  globulin for transport in the blood
• Tryptophan derivative
• Melatonin

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Catecholamines

• Molecules with catechol group
• Hormonal regulators
• Dopamine in hypothalamus inhibits prolactin
  secretion
• Epinephrine (adrenaline) stress reaction
• Synthesized from aa phenylalanine or tyrosine in
  enzymatic reactions

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Peptide Hormone

• Range from 3 amino acids to hundreds of amino
  acids in size.
• Often produced as larger molecular weight
  precursors that are proteolytically cleaved to
  the active form of the hormone.
• Peptide/protein hormones are water soluble.
• Comprise the largest number of hormones perhaps
  in thousands

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Synthesis (peptide Hormone)

• By one or two genes
• e.i. Insulin from single gene
• Glycoprotein hormone from two
  precursors.
• Initial ribosomal product called
• Preprohormones prohormone
  hormone
• mRNA on ribosomal membrane
• Translation of mRNA results in an AAs sequence
  at NH2 terminus of nascent polypeptide.
• Cleavage occurs at sequence
• lys Arg or Arg Aig in Golgi complex
• -Transport it to Rough Endoplasmic Reticulum
• -An energy-requiring process facilitated by
  activity of cellular microfilaments

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Release of peptide hormone

• Peptide hormones and catecholamine, migrate to
  control the plasma membrane in microfilament and
  fuse to membrane by exocytosis
• Control by influx of Ca .
• Secretion at constant rate in pulsetile fashion
  ( Short Bursts)

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• Storage
• After synthesis in rough endoplasmic reticulum
• Packed in membrane vesicles to form granules in
  the Golgi complex as prohormone.
• Glands for peptide hormone contain up to one day
  supply of hormone
• Glands for steroids hormone contain longer time

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Steroid Hormone

• All steroid hormones are derived from cholesterol
  and differ only in the ring structure and side
  chains attached to it.
• All steroid hormones are lipid soluble

Types of steroid hormones
Glucocorticoids cortisol is the major
representative in most mammals Mineralocorticoid
s aldosterone being most prominent Androgens
such as testosterone Estrogens, including
estradiol and estrone Progestogens (also known
a progestins) such as progesterone
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Facts about steroid hormone

• Are not packaged, but synthesized and immediately
  released
• Are all derived from the same parent compound
  Cholesterol
• Enzymes which produce steroid hormones from
  cholesterol are located in mitochondria and
  smooth ER
• Steroids are lipid soluble and thus are freely
  permeable to membranes so are not stored in cells
• Steroid hormones are not water soluble so have to
  be carried in the blood complexed to specific
  binding globulins.
• Corticosteroid binding globulin carries cortisol
• Sex steroid binding globulin carries testosterone
  and estradiol
• In some cases a steroid is secreted by one cell
  and is converted to the active steroid by the
  target cell an example is androgen which
  secreted by the gonad and converted into estrogen
  in the brain

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Steroid Hormone (Cholesterol and Lipid Soluble)

• From small molecular weight precursors
• -Cholesterol Sequential cleavage
  of carbon-carbon bonds
• - Hydroxylation
• Site of Synthesis
• On the gland tissue
• On the Central Nervous System

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• Transport
• Lipid soluble hormones require transport proteins
• albumin and transthyretin (prealbumin)
• specific transport molecules (thyroxine-binding
  globulin)
• only unbound hormone can enter the cell.
• Steroid and thyroid hormones are 99 attached to
  special transport proteins i.e. Binding Carrier
• Circulation in Blood
• From seconds (epinephrine) to hours (insulin), to
  days (reproductive hormone)
• Typical resting concentration very low
• Under stimulated condition
• Peptide hormone 5-100 folds
• Catecholamine 5-100 folds
• Steroids 5-1000 folds

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LH
Extracellularlipoprotein
Cholesterolpool
acetate
ATP
cAMP
cholesterol
PKA
Pregnenolone
3bHSD
Progesterone
P450c17
Androstenedione
17bHSD
TESTOSTERONE
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Feedback Relationship

• Distinguishing characteristics of Endocrine
  System Feedback control production.
• To maintain homeostatic balance for body fluid
  and rate of various metabolic process.
• Example
• 1. Increase of parathyroid hormone sensed by
  (Ca) level
• ? (Ca) (-) Feedback
• ? (Ca) (-) Feedback
• (Complex)- Interaction
• Pituitary- Thyroid hormone
• Adrenal Gonads Hormone

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Type of Feedback

• Cation ( Ca on PTH)
• Metabolites (Glucose on insulin and increase
  glucagon)
• Hormone (Somatostatin on insulin and glucagon)
• Osmolality (Vassopressin, renin, aldosterone)
• Feedback is useful in the assessment of
  pathological states
• Insulin level-Glucose level
• TSH levels- Serum Thyroxine

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Function of Hormones

• Hormonal function involves four Broad domain
• Reproduction Regulate reproductive system
• Maintenance of internal environment
• Growth and development
• Energy production, utilization and storage

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Cont

• Other Function of Hormones
• Regulate gametogenesis
• Control dimorphic, anatomical function and
  behavioral development
• Regulate stability of body fluid and
  electrolytes, heart rate, acid base balance, body
  temperature bone mass, muscle and fat.
• Mediator for substrate flux, conversion of
  calories to energy.
• Mediator in catabolism glucagon of glycogen
  breakdown AAs and FAs to glucose
• Help regulate circadian rhythms ( Sleep/wake
  periods)

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Interaction of Hormones

• Hormone Different effects on various
  tissues at different times of life.

Testosterone

1. Induction of male differentiation of the Wolffian
   ducts.
2. Regression of the embryonic breast.
3. Growth of the male urogenital tract.
4. Induction of the spermatogenesis.
5. Growth of the beard and body hair.
6. Retention of nitrogen
7. Development of prostatic hyperplasia in aging
   males of several species.
8. promotion of muscle growth

• Explanation
• Binding to a high affinity receptor
• Transport of hormone-receptor to nucleus
• Binding to DNA to promote synthesis of mRNA

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Cont

• Insulin
• (prevent hyperglycemia)
• Glucose level
• Glucagon

• One function of multiple Hormones (Insulin)

• A classic example is maintenance of plasma
  glucose within narrow range high enough to
  prevent dysfunction of the central on the one
  hand low enough to prevent the detrimental
  effects of hyperglycemia on the other hand. Such
  regulation could not be accomplished smoothly by
  a single hormone no matter how powerful.

(prevent hypoglycemia)
Catecholamine Cortisol, GH Prevent sever
hyperglycemia
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Mechanism of Steroid Actions

• Steroid Hormone Cell by diffusion
• Binding macromolecules protein (receptors)
• Specific binding sitesin cytoplasm and nucleus
  of the cell
• Acceptor protein on the DNA matrix

Structure of Steroid Nucleus
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Signal Modulations

• These signals or mediators that can modulate the
  rate and extent of a wide variety of biochemical
  reaction and metabolic pathways in almost every
  known cell type.

Biochemical Reaction
Metabolic Pathways
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• Steroid Receptors Characteristic

• First, Binding capacity
• Labeled hormone binding to cells membrane, then
  measuring the bound receptor and the free hormone
  receptors
• High affinity
• Measured by the physiological response

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• Specificity

• Biological Response

• Receptor sites have capacity for recognition to
  the primer hormone rather for other agonistic or
  antagonistic.
• Certain tissue are specific for certain hormone
  e.g. Sex Steroids for (uterus, vagina)

• Hormone receptor binding precedes tissue response

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Control of Hormone Binding

• By Site Activation

• Functional Activation

• Phospohorylation of active site by ATP and
  protein kinase i.e.,Glucocorticoid receptor
• Dephosphorylation by phosphatase i.e., estrogen
  receptors causes the loss of estrogen binding
  activity

• Hormone regulation the
• effective receptor titer
• Down rregulation represent a redubtion
  inhormone-binding activity. i.e.,progesterone
  receptor number decreaseswithin 1 hour after
  progesterone administration.
• Augment receptor titer
• Estrogen and estradiol administration causes
  increase in receptor level
• Induced fil.

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• Functional Activity of Receptors

Feature of Steroid Receptors

• Presents in a small amount in cells. (0.001-0.1
  of total soluble proteins)
• Structurally differ form receptor to another
• High affinity of DNA from hormone

• Estrogen Receptor binds to DNA after
  hormone-receptor complex formation.
• Progesterone receptor
• A subunit of receptor possesses the DNA binding.
• Glucocorticoids Receptors should be saturated
  with the hormone

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Pancreas
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Brief History

• Herophilus, Greek surgeon first described
  pancreas.
• Wirsung discovered the pancreatic duct in 1642
  now called duct of Wirsung.
• Pancreas as a secretory gland was investigated by
  Graaf in 1671.
• R. Fitz established pancreatitis as a disease in
  1889.
• Dr. Whipple performed the first
  pancreatico-duodenectomy in 1935 and refined it
  in 1940 now called Whipple procedure.

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Anatomy of Pancreas

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H- Head of the PancreasN- Neck of the
PancreasB- Body of the PancreasT- Tail of the
PancreasUN- Uncinate

• Neck of the Pancreas

• Head of the Pancreas

• Includes uncinate process
• Flattened structure, 2 3 cm thick
• Attached to the 2nd and 3rd portions of duodenum
  on the right
• Emerges into neck on the left
• Border b/w head neck is determined by GDA
  insertion
• SPDA and IPDA anastamose b/w the duodenum and the
  rt. lateral border

• 2.5 cm in length
• Straddles SMV and PV
• Antero-superior surface supports the pylorus
• Superior mesenteric vessels emerge from the
  inferior border
• Posteriorly, SMV and splenic vein confluence to
  form portal vein
• Posteriorly, mostly no branches to pancreas

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H- Head of the PancreasN- Neck of the
PancreasB- Body of the PancreasT- Tail of the
PancreasUN- Uncinate

• Tail of Pancreas

• Body of Pancreas

• Narrow, short segment
• Lies at the level of the 12th thoracic vertebra
• Ends within the splenic hilum
• Lies in the splenophrenic ligament
• Anteriorly, related to splenic flexure of colon
• May be injured during splenectomy (fistula)

• Elongated, long structure
• Anterior surface, separated from stomach by
  lesser sac
• Posterior surface, related to aorta, lt. adrenal
  gland, lt. renal vessels and upper 1/3rd of lt.
  kidney
• Splenic vein runs embedded in the post. Surface
• Inferior surface is covered by tran. mesocolon

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Histology of Pancreas

• Exocrine Pancreas

• Endocrine Pancreas

• 2 major components acinar cells and ducts
• Constitute 80 to 90 of the pancreatic mass
• Acinar cells secrete the digestive enzymes
• 20 to 40 acinar cells coalesce into a unit called
  the acinus
• Centroacinar cell (2nd cell type in the acinus)
  is responsible for fluid and electrolyte
  secretion by the pancreas

• Ductular system - network of conduits that carry
  the exocrine secretions into the duodenum
• Acinus ? small intercalated ducts ? interlobular
  duct ? pancreatic duct
• Interlobular ducts contribute to fluid and
  electrolyte secretion along with the centroacinar
  cells