endocrine part 1
TRANSCRIPT
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Biochemical Aspect of Endocrine Glands- I.
Biomedical Importance:
1. Survival depends on- ability to adapt to a constantly changing
environment.2. Necessity of intercellular communication.
Definition: Hormone: (Greek - arouse to activity).
Is a substance that is synthesized in one organ and transported by
the circulatory system to act on another tissue. (endocrine)
Overview of Hormonal cascade & Important Endocrine glands:
Environmental/ internal signal
CNS
Limbic System
Hypothalamus
Ant. Pituitary
Target gland
Final hormone
Systemic effects
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Nature of Hormones
Hormones can be divided into five major classes:
(1) amino acid derivatives- (dopamine, catecholamine, and thyroid
hormone)
(2) small neuropeptides- ( gonadotropin-releasing hormone (GnRH),
thyrotropin-releasing hormone (TRH), somatostatin, and vasopressin)
(3) large proteins- (luteinizing hormone (LH), and PTH)
(4) steroid hormones- (cortisol and estrogen that are synthesized from
cholesterol-based precursors)
(5) vitamin derivatives- (retinoids (vitamin A) and vitamin D).
A variety ofpeptide growth factors, most of which act locally,
share actions with hormones.
As a rule, amino acid derivatives and peptide hormones
interact with cell-surface membrane receptors.
Steroids, thyroid hormones, vitamin D, and retinoids are lipid-
soluble and interact with intracellular nuclear receptors.
Classification:
General Features of Hormone Classes
Group I Group II
Types Steroids, iodothyronines,calcitriol, retinoids
Polypeptides, proteins, glycoproteins, catecholamines
Solubility Lipophilic HydrophilicTransport
proteinsYes No
Plasma half-life
Long (hours to days) Short (minutes)
Receptor Intracellular Plasma membrane
Mediator Receptor-hormone complex cAMP, cGMP, Ca2+, metabolites of complexphosphinositols, kinase cascades
RECEPTOR SPECIFICITY & CROSS TALK
Hormone Synthesis & Processing.
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Secretion, Transport & Degradation.
Classification of Hormones byMechanism of Action
I. Hormones that bind to intracellular receptors
Steroid hormonesRetinoic acidThyroid hormones (T3 and T4 )
II. Hormones that bind to cell surface receptors A. The second messenger is cAMP
Adrenergic catecholamines (2, )TSH,FSH, LH, MSH, ACTH, PTH
ADHCalcitoninCRHGlucagonSomatostatin
B. The second messenger is cGMP
Atrial natriuretic factorNitric oxide
C. The second messenger is calcium orphosphatidylinositols (or both)
1 -Adrenergic catecholaminesAngiotensin IIAntidiuretic hormone (vasopressin)Gastrin, CCKGnRHOxytocinThyrotropin-releasing hormone (TRH)
D. The second messenger is a kinase orphosphatase cascade
AdiponectinChorionic somatomammotropinEGF, FGF,IGF 1 & 2, GHErythropoietinLeptinProlactin
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Hormone Action & Signal transduction:
a. A hormonereceptor interaction results in generation of an
intracellular signal:
b. Regulate the activity of a select set of genes,c. Affect the activity of specific proteins.
d. The signal can influence the location of proteins in the cell and
e. Affect general processes such as protein synthesis
I. Intracellular Receptors:-
(Steroid and thyroid hormone("superfamily") Receptors)
Composed of a single polypeptide chain that has, in the
simplest analysis, three distinct domains:
The amino-terminus: In most cases, this region is involved in
activating or stimulating transcription by interacting with other
Membrane Receptor Families and Signaling Pathways
Receptors Effectors Signaling Pathways
G ProteinCoupled Seven-Transmembrane (GPCR)
-Adrenergic, LH, FSH, TSH Gs, adenylate cyclase
Stimulation of cyclic AMP production,protein kinase A
Glucagon PTH, PTHrP ACTH,MSH GHRH, CRH
Ca2+ channels
Calmodulin, Ca2+-dependent kinases
-Adrenergic, Somatostatin Gi
Inhibition of cyclic AMP production
Activation of K+, Ca2+ channels
TRH, GnRH Gq, G11
Phospholipase C, diacylglycerol, IP3, proteinkinase C, voltage-dependent Ca2+ channels
Receptor Tyrosine Kinase
nsulin, IGF-I Tyrosine kinases, IRS MAP kinases, PI 3-kinase; AKT, also knownas protein kinase B, PKB
EGF, NGF Tyrosine kinases, ras Raf, MAP kinases, RSK
Cytokine ReceptorLinked Kinase
GH, PRL JAK, tyrosine kinases STAT, MAP kinase, PI 3-kinase, IRS-1
Serine Kinase
Activin, TGF-, MIS Serine kinase Smads
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components of the transcriptional machinery. The sequence is highly
variable among different receptors.
DNA binding domain: Amino acids in this region are responsible
for binding of the receptor to specific sequences of DNA.
The carboxy-terminus or ligand-binding domain: This is the
region that binds hormone.
In addition to these three core domains, two other important
regions of the receptor protein are a nuclear localization
sequence, which targets the the protein to nucleus, and a
dimerization domain, which is responsible for latching two
receptors together in a form capable of binding DNA.
Hormone-Receptor Binding and Interactions with DNA
When hormone binds to receptor, a characteristic series of events occurs:
Receptor activation is the term used to describe conformational
changes in the receptor induced by binding hormone. The major
consequence of activation is that the receptor becomes competent
to bind DNA.
Activated receptors bind
to "hormone response
elements", which areshort specific sequences of DNA which are located in promoters of
hormone-responsive genes. In most cases, hormone-receptor
complexes bind DNA in pairs.
Transcription from those genes to which the receptor is bound is
affected. Most commonly, receptor binding stimulates transcription.
The hormone-receptor complex thus functions as a transcription
factor.
I. Cell-Surface receptors:-
a. cAMP Mediated.
Synthesised from ATP by adenylyl cyclase located on theinner side of the plasma membrane.
Adenylyl cyclase is activated by a range of signalingmolecules through the activation of adenylyl cyclase
stimulatory G (Gs)-protein-coupled receptors and inhibitedby agonists of adenylyl cyclase inhibitory G (Gi)-protein-coupled receptors.
http://en.wikipedia.org/wiki/Adenylyl_cyclasehttp://en.wikipedia.org/wiki/Gs_alpha_subunithttp://en.wikipedia.org/wiki/Gs_alpha_subunithttp://en.wikipedia.org/wiki/Gs_alpha_subunithttp://en.wikipedia.org/wiki/Adenylyl_cyclase -
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Liver adenylyl cyclase responds more strongly toglucagon, and muscle adenylyl cyclase responds morestrongly to adrenaline.
cAMP decomposition into AMP is catalyzed by the enzymephosphodiesterase.
cyclic AMP works by activating protein kinase A (PKA, a
heterotetrameric molecule consisting of two regulatorysubunits (R) and two catalytic subunits (C).)
a. cGMP Mediated.
Guanylate cyclase (GC) catalyzes cGMP synthesis. This
enzyme converts GTP to cGMP. In turn, peptide hormones
such as the atrial natriuretic factor activate membrane-
bound GC, while soluble GC is typically activated by nitric
oxide to stimulate cGMP synthesis.
cGMP is a common regulator ofion channelconductance,
glycogenolysis, and cellular apoptosis. It also relaxes
smooth muscle tissues & causes vasodilation to increase
blood flow.
a. Calcium/ Phosphatidylinositol.
http://en.wikipedia.org/wiki/Adenosine_monophosphatehttp://en.wikipedia.org/wiki/Phosphodiesterasehttp://en.wikipedia.org/wiki/Guanylate_cyclasehttp://en.wikipedia.org/wiki/Catalysthttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Atrial_natriuretic_factorhttp://en.wikipedia.org/wiki/Atrial_natriuretic_factorhttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Conductancehttp://en.wikipedia.org/wiki/Glycogenolysishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Vasodilatorhttp://en.wikipedia.org/wiki/Blood_flowhttp://en.wikipedia.org/wiki/Adenosine_monophosphatehttp://en.wikipedia.org/wiki/Phosphodiesterasehttp://en.wikipedia.org/wiki/Guanylate_cyclasehttp://en.wikipedia.org/wiki/Catalysthttp://en.wikipedia.org/wiki/Guanosine_triphosphatehttp://en.wikipedia.org/wiki/Atrial_natriuretic_factorhttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Conductancehttp://en.wikipedia.org/wiki/Glycogenolysishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Vasodilatorhttp://en.wikipedia.org/wiki/Blood_flow -
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b. Kinase/ Phosphatase Cascade. (Insulin)
Pathologic Mechanisms of Endocrine disease:1. Hormone Excess.
2. Hormone deficiency.
3. Resistance.
(IGFBP, insulin-like growth factor binding protein; IRS 14, insulin receptor substrate isoforms 14; PI-3 kinase, phosphatidylinositol3-kinase; PTEN, phosphatase and tensin; PKD1, phosphoinositide-dependent kinase; PKB, protein kinase B; SGK, serum andglucocorticoid-regulated kinase; aPKC, atypical protein kinase C; p70S6K, p70 ribosomal protein S6 kinase; mTOR, mammalian targetof rapamycin; GRB2, growth factor receptor binding protein 2; mSOS, mammalian son of sevenless; MEK, MAP kinase kinase andERK kinase; MAP kinase, mitogen-activated protein kinase; mTOR, mammalian Target Of Rapamycin).
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The Glands & Various Axes:
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The Anterior Pituitary
The Master Gland Produces 6 Hormones: PRL, GH, ACTH, TSH, FSH & LH Secreted in a pulsatile manner,(-Hypothalamic RF) . Specific responses in peripheral target tissues. Feedback control.
Hormone deficiency may be inherited or acquired. Diagnoses are often elusive Performing the correct laboratory diagnostic tests.
Anterior Pituitary Hormone Expression and Regulation
Cell Corticotrope Somatotrope Lactotrope Thyrotrope Gonadotrope
Fetal
appearance
6 weeks 8 weeks 12 weeks 12 weeks 12 weeks
Hormone POMC GH PRL TSH FSH LH
Protein Polypeptide Polypeptide Polypeptide Glycoprotein , , subunits
Glycoprotein , , subunits
Amino acids 266 (ACTH 139)
191 199 211 210, 204
Stimulators CRH, AVP, GHRH, ghrelin Estrogen,TRH, VIP
TRH GnRH, activins,estrogen
Inhibitors Glucocorticoids Somatostatin, IGF-I Dopamine T3, T4, dopamine,somatostatin,glucocorticoids
Sex steroids, inhibin
Target gland Adrenal Liver, other tissues Breast, other tissues
Thyroid Ovary, testis
Trophiceffect
Steroidproduction
IGF-I production,growth induction,
insulin antagonism
Milkproduction
T4 synthesis andsecretion
Sex steroidproduction, follicle
growth, germ cellmaturation
Normalrange
ACTH, 422pg/L
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Hormone Test Blood Samples Interpretation
Growthhormone
Insulin tolerance test:
Regular insulin (0.050.15 U/kgIV)
30, 0, 30, 60, 120 min forglucose and GH
Glucose < 40 mg/dL; GH should be >3g/L
GHRH test: 1 g/kg IV 0, 15, 30, 45, 60, 120 min for
GH
Normal response is GH >3 g/L
L-Arginine test: 30 g IV over30 min
0, 30, 60, 120 min for GH Normal response is GH >3 g/L
L-Dopa test: 500 mg PO 0, 30, 60, 120 min for GH Normal response is GH >3 g/L
Prolactin TRH test: 200500 g IV 0, 20, and 60 min for TSHand PRL
Normal prolactin is >2 g/L and increase>200% of baseline
ACTH Insulin tolerance test: regularinsulin (0.050.15 U/kg IV)
30, 0, 30, 60, 90 min forglucose and cortisol
Glucose 7g/dL or to
>20 g/dL
CRH test: 1g/kg ovine CRHIV at 8 A.M.
0, 15, 30, 60, 90, 120 min forACTH and cortisol
Basal ACTH increases 2- to 4-fold andpeaks at 20100 pg/mL
Cortisol levels >2025 g/dL
Metyrapone test: Metyrapone(30 mg/kg) at midnight
Plasma 11-deoxycortisol andcortisol at 8 A.M.; ACTHcan also be measured
Plasma cortisol should be 7.5g/dL or ACTH >75 pg/mL
Standard ACTH stimulationtest: ACTH 1-24 (cosyntropin),0.25 mg IM or IV
0, 30, 60 min for cortisol andaldosterone
Normal response is cortisol >21 g/dL andaldosterone response of >4 ng/dL above
baseline
Low-dose ACTH test: ACTH1-24 (cosyntropin), 1 g IV
0, 30, 60 min for cortisol Cortisol should be >21 g/dL
3-day ACTH stimulation testconsists of 0.25 mg ACTHgiven IV over 8 h each day
Cortisol >21 g/dL
TSH Basal thyroid function tests:T4, T3, TSH
Basal measurements Low free thyroid hormone levels in thesetting of TSH levels that are notappropriately increased indicate pituitaryinsufficiency
TRH test: 200500 g IV 0, 20, 60 min for TSH andPRL
TSH should increase by >5 mU/L unlessthyroid hormone levels are increased
LH, FSH LH, FSH, testosterone, estrogen Basal measurements Basal LH and FSH should be increased inpostmenopausal womenLow testosterone levels in the setting oflow LH and FSH indicate pituitaryinsufficiency
GnRH test: GnRH (100 g) IV 0, 30, 60 min for LH andFSH
In most adults, LH should increase by 10IU/L and FSH by 2 IU/L.
Multiplehormones Combined anterior pituitarytest: GHRH (1 g/kg),CRH (1g/kg), GnRH (100
g), TRH (200 g) are given IV
30, 0, 15, 30, 60, 90, 120min for GH, ACTH, cortisol,LH, FSH, and TSH
Combined or individual releasinghormone responses must be elevated in thecontext of basal target gland hormonevalues and may not be uniformlydiagnostic.
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Pituitary Adenomas: (e.g., acromegaly, prolactinomas, or Cushing's syndrome) .
When a pituitary adenoma is suspected based on MRI, initial hormonal evaluation usually includes
(1) basal PRL; (2) insulin-like growth factor (IGF) I; (3) 24-h urinary free cortisol (UFC) and/or overnightoral dexamethasone (1 mg) suppression test; (4) subunit, FSH, and LH; and (5) thyroid function tests.
Screening Tests for Functional Pituitary Adenomas
Test Comments
Acromegaly Serum IGF-I Interpret IGF-I relative to age- and sex-matchedcontrols
Oral glucose tolerance test with GHobtained at 0, 30, and 60 min
Normal subjects should suppress growth hormone to
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At high concentrations, AVP also causes contraction of smooth muscle in
blood vessels and in the gastrointestinal tract, induces glycogenolysis in the
liver, and potentiates adrenocorticotropic hormone (ACTH) release by
corticotropin-releasing factor. These effects are mediated by V1a or V1b
receptors that are coupled to phospholipase C.
1. Oxytocin.
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Thyroid
Table:Characteristics of Circulating T4 and T3
Hormone Property T4
T3
Serum concentrations
Total hormone 8 g/dL 0.14 g/dL
Fraction of total hormone in the free form 0.02% 0.3%Free (unbound) hormone 21 1012M
6 1012M
Serum half-life 7 d 0.75 d
Fraction directly from the thyroid 100% 20%
Production rate, including peripheral conversion 90 g/d 32 g/d
Intracellular hormone fraction 20% 70%
Relative metabolic potency 0.3 1
Receptor binding 1010M
1011M
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Investigation of primary hypothyroidism
Serum TSH is the investigation of choice; a high TSH level confirms primaryhypothyroidism. A low free T4 level confirms the hypothyroid state (and is
also essential to exclude TSH
deficiency if clinical hypothyroidism is strongly suspected and TSH is normal
or low).
Thyroid and other organ-specific antibodies may be present. Other
abnormalities include the following:
anaemia, which is usually normochromic and normocytic
in type but may be macrocytic (sometimes this is due toassociated pernicious anaemia) or microcytic (in women,
due to menorrhagia)
increased serum aspartate transferase levels, from muscle and/or liver
increased serum creatine kinase levels, with associated myopathy
hypercholesterolaemia and hypertriglyceridaemia
hyponatraemia due to an increase in ADH and impaired free water
clearance.
Hyperthyroidism:
Investigations
Serum TSH is suppressed in hyperthyroidism
(< 0.05 mU/L), except for the very rare instances of TSH
hypersecretion.
A raised free T4 or T3 confirms the diagnosis; T4 is
almost always raised but T3 is more sensitive as there
are occasional cases of isolated T3 toxicosis.